The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance ...The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance between protein synthesis and degradation,is essential for cell functions during plant growth,development,and stress resistance.Nucleus-encoded chloroplast-and mitochondrion-targeted proteins and ER-resident proteins are imported from the cytosol and undergo modification and maturation within their respective organelles.Protein folding is an error-prone process that is influenced by both developmental signals and environmental cues;a number of mechanisms have evolved to ensure efficient import and proper folding and maturation of proteins in plant organelles.Misfolded or damaged proteins with nonnative conformations are subject to degradation via complementary or competing pathways:intraorganelle proteases,the organelle-associated ubiquitin-proteasome system,and the selective autophagy of partial or entire organelles.When proteins in nonnative conformations accumulate,the organellespecific unfolded protein response operates to restore protein homeostasis by reducing protein folding demand,increasing protein folding capacity,and enhancing components involved in proteasome-associated protein degradation and autophagy.This review summarizes recent progress on the understanding of protein quality control in the ER,chloroplasts,and mitochondria in plants,with a focus on common mechanisms shared by these organelles during protein homeostasis.展开更多
Protein quality control(PQC)systems play essential roles in the recognition,refolding and clearance of aberrant proteins,thus ensuring cellular protein homeostasis,or proteostasis.Especially,continued proliferation an...Protein quality control(PQC)systems play essential roles in the recognition,refolding and clearance of aberrant proteins,thus ensuring cellular protein homeostasis,or proteostasis.Especially,continued proliferation and differentiation of stem cells require a high rate of translation;therefore,accurate PQC systems are essential to maintain stem cell function.Growing evidence suggested crucial roles of PQC systems in regulating the stemness and differentiation of stem cells.This review focuses on current knowledge regarding the components of the proteostasis network in stem cells,and the importance of proteostasis in maintaining stem cell identity and regenerative functions.A complete understanding of this process might uncover potential applications in aging intervention and aging-related diseases.展开更多
The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves t...The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).展开更多
ACCELERATED CELL DEATH6 （ACD6） is a multipass membrane protein with an ankyrin domain that acts in a positive feedback loop with the defense signal salicylic acid （SA）. This study implemented biochemical approache...ACCELERATED CELL DEATH6 （ACD6） is a multipass membrane protein with an ankyrin domain that acts in a positive feedback loop with the defense signal salicylic acid （SA）. This study implemented biochemical approaches to infer changes in ACD6 complexes and localization. In addition to forming endoplasmic reticulum （ER）- and plasma membrane （PM）-Iocalized complexes, ACD6 forms soluble complexes, where it is bound to cytosolic HSP70, ubiquitinated, and degraded via the proteasome. Thus, ACD6 constitutively undergoes ER-associated degradation. During SA signaling, the soluble ACD6 pool decreases, whereas the PM pool increases. Similarly, ACD6-1, an activated version of ACD6 that induces SA, is present at low levels in the soluble fraction and high levels in the PM. However, ACD6 variants with amino acid substitutions in the ankyrin domain form aberrant, inactive complexes, are induced by a SA agonist, but show no PM localization. SA signaling also increases the PM pools of FLAGELLIN SENSING2 （FLS2） and BRI1-ASSOClATED RECEPTOR KINASE 1 （BAK1）. FLS2 forms complexes ACD6; both FLS2 and BAK1 require ACD6 for maximal accumulation at the PM in response to SA signaling. A plausible scenario is that SA increases the efficiency of productive folding and/or complex formation in the ER, such that ACD6, together with FLS2 and BAK1, reaches the cell surface to more effectively promote immune responses.展开更多
Dear Editor,The ubiquitin–proteasome system plays a key role in protein quality control by eliminating damaged,misfolded,or unnecessary proteins(Hershko and Ciechanover,1998).Typically,the ubiquitination of a substra...Dear Editor,The ubiquitin–proteasome system plays a key role in protein quality control by eliminating damaged,misfolded,or unnecessary proteins(Hershko and Ciechanover,1998).Typically,the ubiquitination of a substrate is achieved through a cascade of reactions involving ubiquitin-activating(E1),ubiquitinconjugating(E2),and ubiquitin ligase(E3)enzymes(Scheffner et al.,1995).Recent studies have revealed that specific protein features located at the substrate C-terminus,termed Cdegrons,serve as destabilizing signals to recruit cullin–RING ubiquitin ligases(CRLs)for protein ubiquitination and subsequent proteasomal degradation.The substrate receptors(SRs)of CRLs were found to recognize C-degrons in a sequence-specific manner(Koren et al.,2018;Lin et al.,2018).展开更多
The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of ...The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.展开更多
Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Ac...Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.展开更多
基金Projects associated with protein homeostasis in the Liu Lab are financially supported by grants from the National Natural Science Foundation of China(31625004,31872653,and 31800210)the Zhejiang Provincial Talent Program(2019R52005)the 111 Project(B14027).
文摘The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance between protein synthesis and degradation,is essential for cell functions during plant growth,development,and stress resistance.Nucleus-encoded chloroplast-and mitochondrion-targeted proteins and ER-resident proteins are imported from the cytosol and undergo modification and maturation within their respective organelles.Protein folding is an error-prone process that is influenced by both developmental signals and environmental cues;a number of mechanisms have evolved to ensure efficient import and proper folding and maturation of proteins in plant organelles.Misfolded or damaged proteins with nonnative conformations are subject to degradation via complementary or competing pathways:intraorganelle proteases,the organelle-associated ubiquitin-proteasome system,and the selective autophagy of partial or entire organelles.When proteins in nonnative conformations accumulate,the organellespecific unfolded protein response operates to restore protein homeostasis by reducing protein folding demand,increasing protein folding capacity,and enhancing components involved in proteasome-associated protein degradation and autophagy.This review summarizes recent progress on the understanding of protein quality control in the ER,chloroplasts,and mitochondria in plants,with a focus on common mechanisms shared by these organelles during protein homeostasis.
基金This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100)the National Key Research and Development Program of China(2018YFC2000100)the National Natural Science Foundation of China(81625009,81921006,81822018).
文摘Protein quality control(PQC)systems play essential roles in the recognition,refolding and clearance of aberrant proteins,thus ensuring cellular protein homeostasis,or proteostasis.Especially,continued proliferation and differentiation of stem cells require a high rate of translation;therefore,accurate PQC systems are essential to maintain stem cell function.Growing evidence suggested crucial roles of PQC systems in regulating the stemness and differentiation of stem cells.This review focuses on current knowledge regarding the components of the proteostasis network in stem cells,and the importance of proteostasis in maintaining stem cell identity and regenerative functions.A complete understanding of this process might uncover potential applications in aging intervention and aging-related diseases.
基金in part supported by the National Natural Science Foundation of China,Nos.30560042,81160161,81360198,and 82160255Education Department of Jiangxi Province,Nos.GJJ13198 and GJJ170021+1 种基金Jiangxi Provincial Department of Science and Technology,No.20192BAB205043Health and Family Planning Commission of Jiangxi Province,Nos.20181019 and 202210002(all to RX)。
文摘The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).
文摘ACCELERATED CELL DEATH6 （ACD6） is a multipass membrane protein with an ankyrin domain that acts in a positive feedback loop with the defense signal salicylic acid （SA）. This study implemented biochemical approaches to infer changes in ACD6 complexes and localization. In addition to forming endoplasmic reticulum （ER）- and plasma membrane （PM）-Iocalized complexes, ACD6 forms soluble complexes, where it is bound to cytosolic HSP70, ubiquitinated, and degraded via the proteasome. Thus, ACD6 constitutively undergoes ER-associated degradation. During SA signaling, the soluble ACD6 pool decreases, whereas the PM pool increases. Similarly, ACD6-1, an activated version of ACD6 that induces SA, is present at low levels in the soluble fraction and high levels in the PM. However, ACD6 variants with amino acid substitutions in the ankyrin domain form aberrant, inactive complexes, are induced by a SA agonist, but show no PM localization. SA signaling also increases the PM pools of FLAGELLIN SENSING2 （FLS2） and BRI1-ASSOClATED RECEPTOR KINASE 1 （BAK1）. FLS2 forms complexes ACD6; both FLS2 and BAK1 require ACD6 for maximal accumulation at the PM in response to SA signaling. A plausible scenario is that SA increases the efficiency of productive folding and/or complex formation in the ER, such that ACD6, together with FLS2 and BAK1, reaches the cell surface to more effectively promote immune responses.
基金Supplementary material is available at Journal of Molecular Cell Biology online Cryo-EM map of N8CRL2FEM1C has been deposited in the Electron Microscopy Data Bank(EMDB)under accession code EMD-63977The atomic coordinates of N8CRL2FEM1C were deposited into the Protein Data Bank(PDB)under accession number 9UA3+3 种基金We thank Dr Yong-Xiang Gao and the Cryo-EM Center at the University of Science and Technology of China for their technical support with cryo-EM data collection This work is supported by grants from the National Key R&D Program of China(2022YFA1303100)the National Natural Science Foundation of China(22137007 and 92253301)I.K.is supported by the European Research Council(ERC-2020-STG 947709)Israel Science Foundation(ISF,2380/21 and 3096/21)。
文摘Dear Editor,The ubiquitin–proteasome system plays a key role in protein quality control by eliminating damaged,misfolded,or unnecessary proteins(Hershko and Ciechanover,1998).Typically,the ubiquitination of a substrate is achieved through a cascade of reactions involving ubiquitin-activating(E1),ubiquitinconjugating(E2),and ubiquitin ligase(E3)enzymes(Scheffner et al.,1995).Recent studies have revealed that specific protein features located at the substrate C-terminus,termed Cdegrons,serve as destabilizing signals to recruit cullin–RING ubiquitin ligases(CRLs)for protein ubiquitination and subsequent proteasomal degradation.The substrate receptors(SRs)of CRLs were found to recognize C-degrons in a sequence-specific manner(Koren et al.,2018;Lin et al.,2018).
基金supported by National Key R&D Program of China(Grant No.2017YFA0205400,China)the National Natural Science Foundation of China(Grant Nos.81530093 and 81773781,China)+43 种基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-007,China)CAMS Central Public-interest Scientific Institution Basic Research Fund(Grant No.2017PT3104,China)supported by grants of the National Natural Science Foundation of China(Grant No.81874316,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-3-008,China)supported by grants of from the BBSRC and NWCR(Grant Nos.1088 and 1097,UK)supported by grants of NSF(Grant No.IOS-1456023,USA)NIH(Grant No.NIH R21 CA197317,USA)supported by grants of Ministry of Education,Singapore(Grant Nos.MOE2014-T2-1-012 and 2012-T1-001-036,Singapore)supported by grants from the Health Research Council of New Zealandsupported by a Rutherford Discovery Fellowship from the New Zealand government administered by the Royal Society of New Zealandsupported by Funda??o para a Ciência e a Tecnologia(FCT)Research Center Grant UID/BIM/04773/2013 Centre for Biomedical Research 1334a research grant from Liga Portuguesa Contra o Cancro–Núcleo Regional do Sul(LPCC/NRS,Portugal)a FCT 2014 research grant SFRH/BPD/100434/2014a Pro Regem grant PD/BD/114258/2016(Portugal)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)Innovation Network and the British Heart Foundation(PG/16/44/32146,UK)supported by grants from The Howat Foundation Ltd.(UK),Children with Cancer UK,Bloodwise and the Friends of Paul O'Gorman(UK)supported by grants of P-CREATE from Japan Agency for Medical Research and Developmentsupported by grants from the NIH(NIAID,USA),Alex's Lemonade Stand Foundation(USA)and the Samuel Waxman Cancer Research Foundation(USA)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)the "Fondation Centaure"(RTRS),which supports a French transplantation research network,the IHU-Cesti project,the DHU Oncogreffefinancial support managed by the National Research Agency via the"Investment into the Future" program(Grant Nos.ANR-10-IBHU-005and ANR-11-LABX-0016-01,France)supported by Nantes Métropole and Région Pays de la Loire(France)supported by grants of the British Heart Foundation(PG/16/44/32146,UK)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by a joint Ph.D studentship beween the A*Star Institute and the University of Sheffield(UK)supported by funding from the National Institutes of Health National Heart,Lung,and Blood Institute(R01HL141745,USA)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by European Marie Sklodowska Curie ITNProject TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by the National Natural Science Foundation of China(Grant No.81503128,China)CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-008,China)supported by National Institute of Health(NS R01-035546,USA)supported by the National Natural Science Foundation of China(Grant No.81400140,China)CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-011,China)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by Spanish Ministry of Economy and Competitiveness(MINECO)and Fondo Europeo de desarrollo Regional(FEDER)(Grant No.INNPACTO/IPT-2012-0614-010000,Spain)supported by the National Natural Science Foundation of China(Grant Nos.81400286 and 81530093,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-010,China)supported by the National Natural Science Foundation of China(Grant Nos.81472717 and 81673474,China)Beijing Natural Science Foundation(Grant No.7162133,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-007,China)supported by the National Natural Science Foundation of China(Grant No.81703564,China)supported by the National Natural Science Foundation of China(Grant No.81603129,China)
文摘The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
基金supported by grants of 81530093 from the National Natural Science Foundation of China81661128007, 81472653 and 81530080 from National Natural Science Foundation of China+26 种基金supported by grants of 31390431 from the National Natural Science Foundation of Chinasupported by grants of Natural Sciences Foundation of China(31301007 and 81272525)supported by grants of 81622010 from the National Natural Science Foundation of Chinasupported by grants of 81472717 and 81673474 from the National Natural Science Foundation of China81661128007, 81472653 and 81530080 from National Natural Science Foundation of Chinasupported by grants of 81400286 and 81530093 from the National Natural Science Foundation of Chinasupported by grants of 81400140 from the National Natural Science Foundation of Chinasupported by grants of 81503128 from the National Natural Science Foundation of China2016I2M-1-008 from Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciencessupported by grants of 2014CB542103 from National Basic Research Program of China81502473 from National Natural Science Fund for Young Scholars of Chinasupported by US National Institutes of Health grants (CA217510, CA123088, CA099985, CA193136 and CA152470)supported by grants from the Canadian Institutes of Health Research(FRN 123516 and 152954)the Ontario Institute for Cancer Research(ORBiT)supported by NIH grant GM072744Ministry of Science and Technology of China grant 2016YFA0101100the Fundamental Research Fund for the Central University(No. 2017KFQWJX002) from Huazhong University of Science and TechnologyCore fund (Wang2016) for Development of Cell and Gene Therapy Centre of Academy of Medical Sciences,Zhengzhou UniversityThe MRC (MR/M015696/1)2017YFA0205400 from Ministry of Science and Technology of China2016ZX310190 and 2016ZX320014 from Central Public-interest Scientific Institution Basal Research Fund7162133 from Beijing Natural Science Foundation2016-I2M-4-001 from CAMS Innovation Fund for Medical Sciences2016-I2M-1-007 from the CAMS Innovation Fund for Medical Sciences2016-I2M-1010 from the CAMS Innovation Fund for Medical Sciences2016-I2M-1011 from the CAMS Innovation Fund for Medical Sciences2016-I2M-1008 from CAMS Innovation Fund for Medical Sciences
文摘Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.
