Your arteries aren’t just plumbing-they’re also molecular timekeepers.A recent Cell study positions the aorta,the main artery of the body,as a crucial“senohub”,in which“seno”is a shorthand prefix derived from se...Your arteries aren’t just plumbing-they’re also molecular timekeepers.A recent Cell study positions the aorta,the main artery of the body,as a crucial“senohub”,in which“seno”is a shorthand prefix derived from senescence.Far from passive victims of time,these vital conduits actively dispatch“senoproteins”,like unwanted couriers,spreading aging signals throughout the entire physiological landscape.展开更多
Parkinson’s disease（PD）is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compa...Parkinson’s disease（PD）is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta（SNpc）results in a severe and gradual depletion of dopamine content in the striatum,a phenomena that is responsible for the characteristic motor symptoms of this disease.展开更多
The timely and efficient elimination of aberrant proteins and damaged organelles, formed in response to various genetic and environmental stressors, is a vital need for all cells of the body. Recent lines of evidence ...The timely and efficient elimination of aberrant proteins and damaged organelles, formed in response to various genetic and environmental stressors, is a vital need for all cells of the body. Recent lines of evidence point out several non-classical strategies employed by ocular tissues to cope with aberrant constituents generated in the retina and in the retinal pigmented epithelium cells exposed to various stressors. Along with conventional strategies relying upon the intracellular degradation of aberrant constituents through ubiquitin-proteasome and/or lysosome-dependent autophagy proteolysis, two non-conventional mechanisms also contribute to proteostasis maintenance in ocular tissues. An exosome-mediated clearing and a myelinosome-driven secretion mechanism do not require intracellular degradation but provide the export of aberrant constituents and “waste proteins” outside of the cells. The current review is centered on the non-degradative myelinosome-driven secretion mechanism, which operates in the retina of transgenic Huntington’s disease R6/1 model mice. Myelinosome-driven secretion is supported by rare organelles myelinosomes that are detected not only in degenerative Huntington’s disease R6/1 retina but also in various pathological states of the retina and of the retinal pigmented epithelium. The intra-retinal traffic and inter-cellular exchange of myelinosomes was discussed in the context of a dual role of the myelinosome-driven secretion mechanism for proteostasis maintenance in different ocular compartments. Special focus was made on the interplay between degradative and non-degradative strategies in ocular pathophysiology, to delineate potential therapeutic approaches to counteract several vision diseases.展开更多
The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,...The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,the ER is indispensable for the maintenance of proteostasis in the secretory pathway.Within the ER and,in part,in post-ER compartments,the quality control of protein folding is under the regulation of the unfolded protein response(UPR)pathways.The UPR strategy is to enhance protein folding,increase the ER degradation pathway of misfolded proteins,and allow the exit from the ER of only correctly folded proteins.The latter is controlled by the multimeric complex COPII,which also provides some of the components for ER-phagy the only route for the disposal of protein aggregates.In this overview,we wish to contribute to the introduction of new perspectives in the study of the mechanisms underlying the control of proteostasis within the secretory pathway.展开更多
Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function.This complex journey from nascent polypeptides to mature prot...Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function.This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones,folding enzymes,and degradation machineries.Disruptions in this network lead to dysproteostasis,a pathological state implicated in a growing list of human diseases,including neurodegenerative disorders,metabolic syndromes,and cancer.In this review,we provide a comprehensive and multidimensional analysis of protein folding biology,tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics.We explore the historical progression of protein folding research,including landmark discoveries of secondary structure,chaperone biology,and energy landscape theory.We detail the roles of key molecular chaperones across cytosolic,mitochondrial,and endoplasmic reticulum compartments,emphasizing their collaborative actions in protein folding and quality control.We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences,paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity.We then examine therapeutic innovations targeting proteostasis,including chaperone modulators,proteostasis pathway inhibitors,and emerging strategies to increase proteome resilience.By consolidating insights at the molecular,cellular,and systems levels,this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.展开更多
Runt-related transcription factor 2(RUNX2),also called core-binding factor subunit alpha-1(CBFA1),is the bone-specific transcription factor considered the master gene in osteogenesis,contains a crucial RUNT domain for...Runt-related transcription factor 2(RUNX2),also called core-binding factor subunit alpha-1(CBFA1),is the bone-specific transcription factor considered the master gene in osteogenesis,contains a crucial RUNT domain for DNA binding,and is regulated by multiple mechanisms.During the initial stages of osteogenesis,the expression levels of RUNX2 are primarily elevated and then gradually decrease during the formation of osteoblasts and osteocytes.^(1)Abnormal levels of RUNX2 can severely affect osteoblasts and skeletal structure.RUNX2 mutations are linked to cleidocranial dysplasia(CCD),a rare autosomal dominant skeletal disorder characterized by abnormal skeletal phe-notypes.展开更多
Although microgravity has been implicated in osteoporosis,the precise molecular mechanism remains elusive.Here,we found that microgravity might induce mitochondrial protein buildup in skeletal muscle,alongside reduced...Although microgravity has been implicated in osteoporosis,the precise molecular mechanism remains elusive.Here,we found that microgravity might induce mitochondrial protein buildup in skeletal muscle,alongside reduced levels of LONP1 protein.We revealed that disruptions in mitochondrial proteolysis,induced by the targeted skeletal muscle-specific deletion of the essential mitochondrial protease LONP1 or by the acute inducible deletion of muscle LONP1 in adult mice,cause reduced bone mass and compromised mechanical function.Moreover,the bone loss and weakness phenotypes were recapitulated in skeletal musclespecific overexpressing OTC mice,a known protein degraded by LONP1.Mechanistically,mitochondrial proteostasis imbalance triggered the mitochondrial unfolded protein response(UPR^(mt))in muscle,leading to an up-regulation of multiple myokines,including FGF21,which acts as a pro-osteoclastogenic factor.Surprisingly,this mitochondrial proteostasis stress influenced muscle-bone crosstalk independently of ATF4 in skeletal muscle.Furthermore,we established a marked association between serum FGF21 levels and bone health in humans.These findings emphasize the pivotal role of skeletal muscle mitochondrial proteostasis in responding to alterations in loading conditions and in coordinating UPR^(mt) to modulate bone metabolism.展开更多
The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response...The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.展开更多
Protein homeostasis(proteostasis)is a dynamic balance of protein synthesis and degradation.Because of the endosymbiotic origin of chloroplasts and the massive transfer of their genetic information to the nucleus of th...Protein homeostasis(proteostasis)is a dynamic balance of protein synthesis and degradation.Because of the endosymbiotic origin of chloroplasts and the massive transfer of their genetic information to the nucleus of the host cell,many protein complexes in the chloroplasts are constituted from subunits encoded by both genomes.Hence,the proper function of chloroplasts relies on the coordinated expression of chloroplast-and nucleus-encoded genes.The biogenesis and maintenance of chloroplast proteostasis are dependent on synthesis of chloroplast-encoded proteins,import of nucleus-encoded chloroplast proteins from the cytosol,and clearance of damaged or otherwise undesired“old”proteins.This review focuses on the regulation of chloroplast proteostasis,its interactionwith proteostasis of the cytosol,and its retrograde control over nuclear gene expression.We also discuss significant issues and perspectives for future studies and potential applications for improving the photosynthetic performance and stress tolerance of crops.展开更多
Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body fo...Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas.The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear,and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD.However,the formation ofα-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD,possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis.Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation,enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy.Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes,leading to pathological protein aggregation and neurodegeneration in PD.In recent years,multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified.The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.展开更多
Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain pro...Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.展开更多
Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that ar...Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients.展开更多
Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis.Therefore,neural regeneration may be a promising target for treatment of many neurological illnesses.The regenerati...Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis.Therefore,neural regeneration may be a promising target for treatment of many neurological illnesses.The regenerative capacity of adult neural stem cells can be chara cterized by two states:quiescent and active.Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool.Active adult neural stem cells are chara cterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits.This review focuses on diffe rences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis.Furthermore,we discuss the physiological significance and underlying advantages of these diffe rences.Due to the limited number of adult neural stem cells studies,we refe rred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms.展开更多
Proteostasis(protein homeostasis) ensures precise adjustment of cellular demand to proteins in the stress conditions, which is essential in the maintenance of health environment inside cells and is indispensable for t...Proteostasis(protein homeostasis) ensures precise adjustment of cellular demand to proteins in the stress conditions, which is essential in the maintenance of health environment inside cells and is indispensable for the life of organisms1.展开更多
A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse.Therapeutic options are currently being ex...A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse.Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease,including synthesis,chaperone-assisted folding and trafficking,and degradation via the proteasome and autophagy pathways.Other therapies,like mTOR inhibitors and activators of the heat shock response,can rebalance the entire proteostatic network.However,there are major challenges that impact the development of novel therapies,including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response.A notable development is the creation of collaborative ecosystems that include patients,clinicians,basic and translational researchers,foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent,reverse or delay the progression of neurodegenerative proteinopathies.展开更多
Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here...Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and senescence.To this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.展开更多
Chloroplasts overproduce reactive oxygen species(ROS)under unfavorable environmental conditions,and these ROS are implicated in both signaling and oxidative damage.There is mounting evidence for their roles in transla...Chloroplasts overproduce reactive oxygen species(ROS)under unfavorable environmental conditions,and these ROS are implicated in both signaling and oxidative damage.There is mounting evidence for their roles in translating environmental fluctuations into distinct physiological responses,but their targets,signaling cascades,and mutualism and antagonism with other stress signaling cascades and within ROS signaling remain poorly understood.Great efforts made in recent years have shed new light on chloroplast ROS-directed plant stress responses,from ROS perception to plant responses,in conditional mutants of Arabidopsis thaliana or under various stress conditions.Some articles have also reported the mechanisms underlying the complexity of ROS signaling pathways,with an emphasis on spatiotemporal regulation.ROS and oxidative modification of affected target proteins appear to induce retrograde signaling pathways to maintain chloroplast protein quality control and signaling at a whole-cell level using stress hormones.This review focuses on these seemingly interconnected chloroplast-to-nucleus retrograde signaling pathways initiated by ROS and ROS-modified target molecules.We also discuss future directions in chloroplast stress research to pave the way for discovering new signaling molecules and identifying intersectional signaling components that interact in multiple chloroplast signaling pathways.展开更多
Cells have different sets of molecules for performing an array of physiological functions.Nucleic acids have stored and carried the information throughout evolution,whereas proteins have been attributed to performing ...Cells have different sets of molecules for performing an array of physiological functions.Nucleic acids have stored and carried the information throughout evolution,whereas proteins have been attributed to performing most of the cellular functions.To perform these functions,proteins need to have a unique conformation and a definite lifespan.These attributes are achieved by a highly coordinated protein quality control(PQC)system comprising chaperones to fold the proteins in a proper threedimensional structure,ubiquitin-proteasome system for selective degradation of proteins,and autophagy for bulk clearance of cell debris.Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery,leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions.However,modulating the expression and functional efficiency of molecular chaperones,E3 ubiquitin ligases,and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects.Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions.The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.展开更多
Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obst...Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.展开更多
High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological ...High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrAZ remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is impticated in unfotded protein response. ｜n highly secre- tory cells of the retinal pigmented epithelia, endoplasmic reticulum （ER） stress upregulated HtrA1. HtrA1 co-localized with vimen- tin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions dis- played reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mam- malian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.展开更多
文摘Your arteries aren’t just plumbing-they’re also molecular timekeepers.A recent Cell study positions the aorta,the main artery of the body,as a crucial“senohub”,in which“seno”is a shorthand prefix derived from senescence.Far from passive victims of time,these vital conduits actively dispatch“senoproteins”,like unwanted couriers,spreading aging signals throughout the entire physiological landscape.
基金supported by FONDECYT-11140738 (G.M.).Michael J. Fox Foundation for Parkinson Research, Ring Initiative ACT1109+1 种基金FONDEF D11I1007 (C.H.). We also thank, FONDECYT-1140549Millennium Institute P09-015-F, COPEC-UC, and Frick Foundation (C.H.). V.C. is supported by CONICYT fellowship
文摘Parkinson’s disease（PD）is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta（SNpc）results in a severe and gradual depletion of dopamine content in the striatum,a phenomena that is responsible for the characteristic motor symptoms of this disease.
文摘The timely and efficient elimination of aberrant proteins and damaged organelles, formed in response to various genetic and environmental stressors, is a vital need for all cells of the body. Recent lines of evidence point out several non-classical strategies employed by ocular tissues to cope with aberrant constituents generated in the retina and in the retinal pigmented epithelium cells exposed to various stressors. Along with conventional strategies relying upon the intracellular degradation of aberrant constituents through ubiquitin-proteasome and/or lysosome-dependent autophagy proteolysis, two non-conventional mechanisms also contribute to proteostasis maintenance in ocular tissues. An exosome-mediated clearing and a myelinosome-driven secretion mechanism do not require intracellular degradation but provide the export of aberrant constituents and “waste proteins” outside of the cells. The current review is centered on the non-degradative myelinosome-driven secretion mechanism, which operates in the retina of transgenic Huntington’s disease R6/1 model mice. Myelinosome-driven secretion is supported by rare organelles myelinosomes that are detected not only in degenerative Huntington’s disease R6/1 retina but also in various pathological states of the retina and of the retinal pigmented epithelium. The intra-retinal traffic and inter-cellular exchange of myelinosomes was discussed in the context of a dual role of the myelinosome-driven secretion mechanism for proteostasis maintenance in different ocular compartments. Special focus was made on the interplay between degradative and non-degradative strategies in ocular pathophysiology, to delineate potential therapeutic approaches to counteract several vision diseases.
基金This work was supported by POR FERS Regione Campania 2014–2020 ASSE 1 O.S 1.2grant System Innovation for Cancer Early Diagnosis(SICED).
文摘The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,the ER is indispensable for the maintenance of proteostasis in the secretory pathway.Within the ER and,in part,in post-ER compartments,the quality control of protein folding is under the regulation of the unfolded protein response(UPR)pathways.The UPR strategy is to enhance protein folding,increase the ER degradation pathway of misfolded proteins,and allow the exit from the ER of only correctly folded proteins.The latter is controlled by the multimeric complex COPII,which also provides some of the components for ER-phagy the only route for the disposal of protein aggregates.In this overview,we wish to contribute to the introduction of new perspectives in the study of the mechanisms underlying the control of proteostasis within the secretory pathway.
基金funded by the Norwegian Research Council(303353)the Norwegian Cancer Society(247110)+1 种基金Helse Sør-Øst(2021022,2022041,2023078)Anders Jahre fund(102583101,10,000)。
文摘Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function.This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones,folding enzymes,and degradation machineries.Disruptions in this network lead to dysproteostasis,a pathological state implicated in a growing list of human diseases,including neurodegenerative disorders,metabolic syndromes,and cancer.In this review,we provide a comprehensive and multidimensional analysis of protein folding biology,tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics.We explore the historical progression of protein folding research,including landmark discoveries of secondary structure,chaperone biology,and energy landscape theory.We detail the roles of key molecular chaperones across cytosolic,mitochondrial,and endoplasmic reticulum compartments,emphasizing their collaborative actions in protein folding and quality control.We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences,paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity.We then examine therapeutic innovations targeting proteostasis,including chaperone modulators,proteostasis pathway inhibitors,and emerging strategies to increase proteome resilience.By consolidating insights at the molecular,cellular,and systems levels,this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.
基金supported by Valenti FUR(University of Verona),Dalle Carbonare FUR(University of Verona),and the Department of Excellence 2023/2027,MUR,Italy.J.P.acknowledges funding from FCT-Fundacao para a Ciencia e a Tecnologia(Portugal)and FEDER through grant 2022.01199.PTDC.
文摘Runt-related transcription factor 2(RUNX2),also called core-binding factor subunit alpha-1(CBFA1),is the bone-specific transcription factor considered the master gene in osteogenesis,contains a crucial RUNT domain for DNA binding,and is regulated by multiple mechanisms.During the initial stages of osteogenesis,the expression levels of RUNX2 are primarily elevated and then gradually decrease during the formation of osteoblasts and osteocytes.^(1)Abnormal levels of RUNX2 can severely affect osteoblasts and skeletal structure.RUNX2 mutations are linked to cleidocranial dysplasia(CCD),a rare autosomal dominant skeletal disorder characterized by abnormal skeletal phe-notypes.
基金supported by grants from the National Natural Science Foundation of China(no.82372497 to Z.Zhu,no.82072393 to Y.Q,and nos.91857105,31922033,32071136,and 32100922 to Z.G.and T.F.)Ministry of Science and Technology of China(National Key R&D Program of China 2018YFA0800700 and 2022YFA0806000 to Z.G.)+2 种基金Natural Science Foundation of Jiangsu Province(sec20230146 to Y.Y.)Fundamental Research Funds for the Central Universities(021414380517 to T.F.and 021414380511,021414380529,and 021414380524 to Z.G.)China Postdoctoral Science Foundation(2023M731633 to Y.Y.)。
文摘Although microgravity has been implicated in osteoporosis,the precise molecular mechanism remains elusive.Here,we found that microgravity might induce mitochondrial protein buildup in skeletal muscle,alongside reduced levels of LONP1 protein.We revealed that disruptions in mitochondrial proteolysis,induced by the targeted skeletal muscle-specific deletion of the essential mitochondrial protease LONP1 or by the acute inducible deletion of muscle LONP1 in adult mice,cause reduced bone mass and compromised mechanical function.Moreover,the bone loss and weakness phenotypes were recapitulated in skeletal musclespecific overexpressing OTC mice,a known protein degraded by LONP1.Mechanistically,mitochondrial proteostasis imbalance triggered the mitochondrial unfolded protein response(UPR^(mt))in muscle,leading to an up-regulation of multiple myokines,including FGF21,which acts as a pro-osteoclastogenic factor.Surprisingly,this mitochondrial proteostasis stress influenced muscle-bone crosstalk independently of ATF4 in skeletal muscle.Furthermore,we established a marked association between serum FGF21 levels and bone health in humans.These findings emphasize the pivotal role of skeletal muscle mitochondrial proteostasis in responding to alterations in loading conditions and in coordinating UPR^(mt) to modulate bone metabolism.
基金supported by the Natural Science Foundation of Shaanxi Province(Key Program),No.2021JZ-60(to HZ)。
文摘The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.
基金funded by the National Natural Science Foundation of China(NSFC32070299,32270285)+2 种基金the Shanghai Pujiang Program(20PJ1405600)the Shanghai Collaborative Innovation Center of Agri-Seeds(ZXWH2150201/014)the Partner Group program of the Max Planck Society to G.-Z.W.
文摘Protein homeostasis(proteostasis)is a dynamic balance of protein synthesis and degradation.Because of the endosymbiotic origin of chloroplasts and the massive transfer of their genetic information to the nucleus of the host cell,many protein complexes in the chloroplasts are constituted from subunits encoded by both genomes.Hence,the proper function of chloroplasts relies on the coordinated expression of chloroplast-and nucleus-encoded genes.The biogenesis and maintenance of chloroplast proteostasis are dependent on synthesis of chloroplast-encoded proteins,import of nucleus-encoded chloroplast proteins from the cytosol,and clearance of damaged or otherwise undesired“old”proteins.This review focuses on the regulation of chloroplast proteostasis,its interactionwith proteostasis of the cytosol,and its retrograde control over nuclear gene expression.We also discuss significant issues and perspectives for future studies and potential applications for improving the photosynthetic performance and stress tolerance of crops.
基金The Singapore National Medical Research Council(NMRC)grants including STaR and a clinical translational research program in Parkinson’s disease.
文摘Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas.The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear,and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD.However,the formation ofα-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD,possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis.Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation,enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy.Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes,leading to pathological protein aggregation and neurodegeneration in PD.In recent years,multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified.The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.
基金the National Natural Science Foundation of China(81903666 and 31930015)the Chinese Academy of Sciences(XDB31000000,KFJ-STS-SCYD-304,and K.C.Wong Education Foundation,China)+4 种基金the Science and Technology Department of Yunnan Province (202101AT070301,2019ZF003,202002AA100007,202003AD150008,and 2019FB103China)Project of Innovative Research Team of Yunnan Province(2019HC005China)the Department of Industry and Information Technology of Yunnan Province (2019-YT-053,China)。
文摘Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.
基金supported by research grants to LMI from University of Buenos Aires(UBACyT)the Agencia Nacional de Promoción Científica y Tecnológica(ANPCyT)under grants PICT 2015-0975 and PICT 2017-2140。
文摘Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients.
基金supported by the National Natural Science Foundation of China,No.82171336(to XX)。
文摘Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis.Therefore,neural regeneration may be a promising target for treatment of many neurological illnesses.The regenerative capacity of adult neural stem cells can be chara cterized by two states:quiescent and active.Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool.Active adult neural stem cells are chara cterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits.This review focuses on diffe rences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis.Furthermore,we discuss the physiological significance and underlying advantages of these diffe rences.Due to the limited number of adult neural stem cells studies,we refe rred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms.
文摘Proteostasis(protein homeostasis) ensures precise adjustment of cellular demand to proteins in the stress conditions, which is essential in the maintenance of health environment inside cells and is indispensable for the life of organisms1.
文摘A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse.Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease,including synthesis,chaperone-assisted folding and trafficking,and degradation via the proteasome and autophagy pathways.Other therapies,like mTOR inhibitors and activators of the heat shock response,can rebalance the entire proteostatic network.However,there are major challenges that impact the development of novel therapies,including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response.A notable development is the creation of collaborative ecosystems that include patients,clinicians,basic and translational researchers,foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent,reverse or delay the progression of neurodegenerative proteinopathies.
基金supported by the National Key Research and Development Program of China(2020YFA0804000,2022YFA1103700,2020YFA0112200,2021YFF1201000,the STI2030-Major Projects-2021ZD0202400,2022YFA1103800)the National Natural Science Foundation of China(82201714,81921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,82071588,32000500,82271600,82001477,82201727)+12 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16000000)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation(Z190019)the Fellowship of China Postdoctoral Science Foundation(2022M712216)the Project for Technology Development of Beijing-affiliated Medical Research Institutes(11000023T000002036310)the Pilot Project for Public Welfare Development and Reform of Beijing-affiliated Medical Research Institutes(11000022T000000461062)Youth Innovation Promotion Association of CAS(E1CAZW0401,2022083,2023092)Young Elite Scientists Sponsorship Program by CAST(YESS20200012,YESS20210002)the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CAS-WX2022SDC-XK14,CASWX2021SF-0101)New Cornerstone Science Foundation through the XPLORER PRIZE(2021-1045)Excellent Young Talents Program of Capital Medical University(12300927)Excellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher Team(BPHR202203105)Beijing Hospitals Authority Youth Programme(QML20230806)。
文摘Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and senescence.To this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.
基金Research in the Kim laboratory has been supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(grant XDB27040102)the 100-Talent Program of the Chinese Academy of Sciences,and the National Natural Science Foundation of China(grant 31871397 to C.K.).
文摘Chloroplasts overproduce reactive oxygen species(ROS)under unfavorable environmental conditions,and these ROS are implicated in both signaling and oxidative damage.There is mounting evidence for their roles in translating environmental fluctuations into distinct physiological responses,but their targets,signaling cascades,and mutualism and antagonism with other stress signaling cascades and within ROS signaling remain poorly understood.Great efforts made in recent years have shed new light on chloroplast ROS-directed plant stress responses,from ROS perception to plant responses,in conditional mutants of Arabidopsis thaliana or under various stress conditions.Some articles have also reported the mechanisms underlying the complexity of ROS signaling pathways,with an emphasis on spatiotemporal regulation.ROS and oxidative modification of affected target proteins appear to induce retrograde signaling pathways to maintain chloroplast protein quality control and signaling at a whole-cell level using stress hormones.This review focuses on these seemingly interconnected chloroplast-to-nucleus retrograde signaling pathways initiated by ROS and ROS-modified target molecules.We also discuss future directions in chloroplast stress research to pave the way for discovering new signaling molecules and identifying intersectional signaling components that interact in multiple chloroplast signaling pathways.
文摘Cells have different sets of molecules for performing an array of physiological functions.Nucleic acids have stored and carried the information throughout evolution,whereas proteins have been attributed to performing most of the cellular functions.To perform these functions,proteins need to have a unique conformation and a definite lifespan.These attributes are achieved by a highly coordinated protein quality control(PQC)system comprising chaperones to fold the proteins in a proper threedimensional structure,ubiquitin-proteasome system for selective degradation of proteins,and autophagy for bulk clearance of cell debris.Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery,leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions.However,modulating the expression and functional efficiency of molecular chaperones,E3 ubiquitin ligases,and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects.Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions.The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.
基金supported by National Natural Science Foundation of China(Nos.82073780 and 82273868,China)Shanghai Municipal Natural Science Foundation(No.19ZR1406200,China)。
文摘Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.
文摘High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrAZ remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is impticated in unfotded protein response. ｜n highly secre- tory cells of the retinal pigmented epithelia, endoplasmic reticulum （ER） stress upregulated HtrA1. HtrA1 co-localized with vimen- tin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions dis- played reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mam- malian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.
