Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells...Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.展开更多
Protein post-translational modifications(PTMs),such as ubiquitination,phosphorylation,and small ubiquitin-like modifier(SUMO)ylation,are crucial for regulating protein stability,activity,subcellular localization,and b...Protein post-translational modifications(PTMs),such as ubiquitination,phosphorylation,and small ubiquitin-like modifier(SUMO)ylation,are crucial for regulating protein stability,activity,subcellular localization,and binding with cofactors.Such modifications remarkably increase the variety and complexity of proteomes,which are essential for regulating numerous cellular and physiological processes.The regulation of auxin signaling is finely tuned in time and space to guide various plant growth and development.Accumulating evidence indicates that PTMs play critical roles in auxin signaling regulations.Thus,a thorough and systematic review of the functions of PTMs in auxin signal transduction will improve our profound comprehension of the regulation mechanism of auxin signaling and auxin-mediated various processes.This review discusses the progress of protein ubiquitination,phosphorylation,histone acetylation and methylation,SUMOylation,and S-nitrosylation in the regulation of auxin signaling.展开更多
Protein-based therapeutics (PPTs) are drugs used to treat a variety of different conditions in the human body by alleviating enzymatic deficiencies, augmenting other proteins and drugs, modulating signal pathways, and...Protein-based therapeutics (PPTs) are drugs used to treat a variety of different conditions in the human body by alleviating enzymatic deficiencies, augmenting other proteins and drugs, modulating signal pathways, and more. However, many PPTs struggle from a short half-life due to degradation caused by irreversible protein aggregation in the bloodstream. Currently, the most researched strategies for improving the efficiency and longevity of PPTs are post-translational modifications (PTMs). The goal of our research was to determine which type of PTM increases longevity the most for each of three commonly-used therapeutic proteins by comparing the docking scores (DS) and binding free energies (BFE) from protein aggregation and reception simulations. DS and BFE values were used to create a quantitative index that outputs a relative number from −1 to 1 to show reduced performance, no change, or increased performance. Results showed that methylation was the most beneficial for insulin (p < 0.1) and human growth hormone (p < 0.0001), and both phosphorylation and methylation were somewhat optimal for erythropoietin (p < 0.1 and p < 0.0001, respectively). Acetylation consistently provided the worst benefits with the most negative indices, while methylation had the most positive indices throughout. However, PTM efficacy varied between PPTs, supporting previous studies regarding how each PTM can confer different benefits based on the unique structures of recipient proteins.展开更多
The biosynthesis of prostanoids is involved in both physiological and pathological processes.The expression of prostaglandin-endoperoxide synthase 2(PTGS2;also known as COX-2)has been traditionally associated to the o...The biosynthesis of prostanoids is involved in both physiological and pathological processes.The expression of prostaglandin-endoperoxide synthase 2(PTGS2;also known as COX-2)has been traditionally associated to the onset of several pathologies,from inflammation to cardiovascular,gastrointestinal and oncologic events.For this reason,the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions.In addition to the classic non-steroidal anti-inflammatory drugs,selective and specific PTGS2 inhibitors,termed coxibs,have been generated and widely used.PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1,and it accounts for the elevated prostanoid synthesis that accompanies several pathologies.The main regulation of PTGS2 occurs at the transcription level.In addition to this,the stability of the mRNA is finely regulated through the interaction with several cytoplasmic elements,ranging from specificmicroR NAs to proteins that control mR NA degradation.Moreover,the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation via proteasomal and non-proteasomal mechanisms.Among these modifications,phosphorylation,glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the proinflammatory condition appear to be the main changes.Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress.Finally,these modifications can be used as biomarkers to establish correlations with other parameters,including the immunomodulation dependent on molecular pathological epidemiology determinants,which may provide a better frame for potential therapeutic interventions.展开更多
Deficits in intrinsic neuronal capacities in the spinal cord,a lack of growth support,and suppression of axonal outgrowth by inhibitory molecules mean that spinal cord injury almost always has devastating consequences...Deficits in intrinsic neuronal capacities in the spinal cord,a lack of growth support,and suppression of axonal outgrowth by inhibitory molecules mean that spinal cord injury almost always has devastating consequences.As such,one of the primary targets for the treatment of spinal cord injury is to develop strategies to antagonize extrinsic or intrinsic axonal growth-inhibitory factors or enhance the factors that support axonal growth.Among these factors,a series of individual protein level disorders have been identified during the generation of axons following spinal cord injury.Moreover,an increasing number of studies have indicated that post-translational modifications of these proteins have important implications for axonal growth.Some researchers have discovered a variety of post-translational modifications after spinal cord injury,such as tyrosination,acetylation,and phosphorylation.In this review,we reviewed the post-translational modifications for axonal growth,functional recovery,and neuropathic pain after spinal cord injury,a better understanding of which may elucidate the dynamic change of spinal cord injury-related molecules and facilitate the development of a new therapeutic strategy for spinal cord injury.展开更多
The 57 kDa antigen recognized by the Ki-1 antibody,is also known as intracellular hyaluronic acid binding protein 4 and shares 40.7%identity and 67.4%similarity with serpin mRNA binding protein 1,which is also named C...The 57 kDa antigen recognized by the Ki-1 antibody,is also known as intracellular hyaluronic acid binding protein 4 and shares 40.7%identity and 67.4%similarity with serpin mRNA binding protein 1,which is also named CGI-55,or plasminogen activator inhibitor type-1-RNA binding protein-1,indicating that they might be paralog proteins,possibly with similar or redundant functions in human cells.Through the identification of their protein interactomes,both regulatory proteins have been functionally implicated in transcriptional regulation,mRNA metabolism,specifically RNA splicing,the regulation of mRNA stability,especially,in the context of the progesterone hormone response,and the DNA damage response.Both proteins also show a complex pattern of post-translational modifications,involving Ser/Thr phosphorylation,mainly through protein kinase C,arginine methylation and SUMOylation,suggesting that their functions and locations are highly regulated.Furthermore,they show a highly dynamic cellular localization pattern with localizations in both the cytoplasm and nucleus as well as punctuated localizations in both granular cytoplasmic protein bodies,upon stress,and nuclear splicing speckles.Several reports in the literature show altered expressions of both regulatory proteins in a series of cancers as well as mutations in their genes that may contribute to tumorigenesis.This review highlights important aspects of the structure,interactome,post-translational modifications,sub-cellular localization and function of both regulatory proteins and further discusses their possible functions and their potential as tumor markers in different cancer settings.展开更多
Mitochondria are essential for cell growth,fission,differentiation,and survival,particularly in undivided cells with high energy requirements,such as cardiomyocytes.The morphology and position of mitochondria change w...Mitochondria are essential for cell growth,fission,differentiation,and survival,particularly in undivided cells with high energy requirements,such as cardiomyocytes.The morphology and position of mitochondria change with the activity of mitochondrial fission proteins and mitochondrial fusion proteins.These regulatory mechanisms substan-tially affect cardiomyocyte energy supply and normal function.In mitochondrial fission,dynamin-related protein 1(Drp1)is involved in the separation and degradation of damaged mitochondria,and accurately regulates mitochon-drial renewal and number.Recent studies have revealed a variety of post-translational modification(PTMs)of Drp1,including phosphorylation,SUMOylation,acetylation,O-GlcNAcylation,and S-sulfhydration.These modifications ensure that Drp1 continues to function normally in various signaling pathways,by modulating its activity,stability,and subcellular localization.This article provides an overview of the relationship between Drp1 PTMs and cardiovascular diseases such as heart failure,myocardial infarction,and myocardial ischemia-reperfusion,and describes how these modifications can be targeted and regulated,to help guide cardiovascular disease treatment.展开更多
Post-translational modifications are rapid, effective and reversible ways to regulate protein stability, localization, function, and their interactions with other molecules. Post-translational modifications usually oc...Post-translational modifications are rapid, effective and reversible ways to regulate protein stability, localization, function, and their interactions with other molecules. Post-translational modifications usually occur as chemical modifications at amino acid residues, including SUMOylation, phosphorylation, palmitoylation, acetylation, etc. These complex biochemical modifications tightly regulate and control a variety of cellular processes. Several forms of post-translational modifications of huntingtin （Htt） have been described. These modifications affect Htt metabolism, protein-protein interactions and cellular toxicity. Cleavage and clearance of mutant Htt, and the interactions between mutant Htt and other cellular proteins are important biochemical events leading to Huntington＇s disease （HD）. Therefore, identifying signaling pathways of Htt modification and evaluating the significance of Htt modifications would lead to a better understanding of the normal function of wild-type Htt and the pathogenic mechanisms of mutant Htt.展开更多
Replication of hepatitis C virus(HCV)depends on the interaction of viral proteins with various host cellular proteins and signalling pathways.Similar to cellular proteins,post-translational modifications(PTMs)of HCV p...Replication of hepatitis C virus(HCV)depends on the interaction of viral proteins with various host cellular proteins and signalling pathways.Similar to cellular proteins,post-translational modifications(PTMs)of HCV proteins are essential for proper protein function and regulation,thus,directly affecting viral life cycle and the generation of infectious virus particles.Cleavage of the HCV polyprotein by cellular and viral proteases into more than 10 proteins represents an early protein modification step after translation of the HCV positivestranded RNA genome.The key modifications include the regulated intramembranous proteolytic cleavage of core protein,disulfide bond formation of core,glycosylation of HCV envelope proteins E1 and E2,methylation of nonstructural protein 3(NS3),biotinylation of NS4A,ubiquitination of NS5B and phosphorylation of core and NS5B.Other modifications like ubiquitination of core and palmitoylation of core and NS4B proteins have been reported as well.For some modifications such as phosphorylation of NS3 and NS5A and acetylation of NS3,we have limited understanding of their effects on HCV replication and pathogenesis while the impact of other modifications is far from clear.In this review,we summarize the available information on PTMs of HCV proteins and discuss their relevance to HCV replication and pathogenesis.展开更多
Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications(PTMs).PTMs alter the conformation,the stability,the localization,and henc...Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications(PTMs).PTMs alter the conformation,the stability,the localization,and hence the pattern of interactions of the targeted protein.Cell pathways involve the activation of enzymes,like kinases,ligases and transferases,that,once activated,act on many proteins simultaneously,altering the state of the cell and triggering the processes they are involved in.Viruses enter a balanced system and hijack the cell,exploiting the potential of PTMs either to activate viral encoded proteins or to alter cellular pathways,with the ultimate consequence to perpetuate through their replication.Human T-lymphotropic virus type 1(HTLV-1)is known to be highly oncogenic and associates with adult T-cell leukemia/lymphoma,HTLV-1-associated myelopathy/tropical spastic paraparesis and other inflammatory pathological conditions.HTLV-1 protein activity is controlled by PTMs and,in turn,viral activity is associated with the modulation of cellular pathways based on PTMs.More knowledge is acquired about the PTMs involved in the activation of its proteins,like Tax,Rex,p12,p13,p30,HTLV-I basic leucine zipper factorand Gag.However,more has to be understood at the biochemical level in order to counteract the associated fatal outcomes.This review will focus on known PTMs that directly modify HTLV-1 components and on enzymes whose activity is modulated by viral proteins.展开更多
In the present work, computational analyses were applied to study the subcellular localiza-tion and posttranslational modifications of hu-man prion proteins (PrPs). The tentative location of prion protein was determin...In the present work, computational analyses were applied to study the subcellular localiza-tion and posttranslational modifications of hu-man prion proteins (PrPs). The tentative location of prion protein was determined to be in the nu-cleolus inside the nucleus by the following bio-informatics tools: Hum-PLoc, Euk-PLoc and Nuc-PLoc. Based on our results signal peptides with average of 22 base pairs in N-terminal were identified in human PrPs. This theoretical study demonstrates that PrP is post-translationally modified by: 1) attachment of two N-linked complex carbohydrate moieties (N181 and N197), 2) attachmet of glycosylphosphatidylinositol (GPI) at serine 230 and 3) formation of two di-sulfide bonds between “6–22” and “179–214” cysteines. Furthermore, ten protein kinase phosphorylation sites were predicted in human PrP. The above-noted phosphorylation was car-ried out by PKC and CK2. By using bioinfor-matics tools, we have shown that computation-ally human PrPs locate particularly into the nu-cleolus.展开更多
As the most abundant and essential structural protein in the human body,collagen is ubiquitously present in the interstitium of nearly all solid organs,playing a crucial role in maintaining the structural integrity an...As the most abundant and essential structural protein in the human body,collagen is ubiquitously present in the interstitium of nearly all solid organs,playing a crucial role in maintaining the structural integrity and functional stability of human tissues and organs.Disorders associated with collagen structure and metabolisms impose a significant burden on society and healthcare systems.Posttranslational modifications(PTMs)are essential steps in collagen metabolism,and recent studies have indicated that aberrant regulation of PTMs plays a pivotal role in the pathogenesis and progress of collagen-related disorders,including liver,kidney,heart,lung,and skin fibrosis,as well as keloid.This review provides a comprehensive summary of the regulatory mechanisms of both traditional and novel PTMs in collagen metabolism and collagen-related diseases.Furthermore,we summarize the drugs that modulate PTMs and their effects,with the aim of elucidating the pathophysiology of collagen-related diseases and provide new insights for their diagnosis,prevention,and treatment.展开更多
Osteogenesis is driven by the differentiation of osteoblasts and the mineralization of the bone matrix,with oral-derived stem cells playing a significant role in this process.Various post-translational modifications(P...Osteogenesis is driven by the differentiation of osteoblasts and the mineralization of the bone matrix,with oral-derived stem cells playing a significant role in this process.Various post-translational modifications(PTMs),such as phosphorylation,acetylation,methylation,and glycosylation,regulate osteogenic differentiation(OD).These modifications influence the expression of osteogenic genes by modulating the activity of key transcription factors like runt-related transcription factor 2 and osterix.While the molecular mechanisms behind OD are increasingly understood,many questions remain,particularly regarding how PTMs control the specificity and efficiency of stem cell differentiation.Recent research into these modifications has underscored the potential of stem cell therapy for bone regeneration and treating bone-related diseases.This review summarizes the role of PTMs in the OD of oral-derived stem cells,discusses their clinical applications,and suggests future research directions.展开更多
Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine...Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine-specific demethylase 1)is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4(H3K4)and histone H3 lysine K9(H3K9).This ability of LSD1 allows it to inhibit or activate transcription.LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of thesePTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders,neurological disorders, cardiovascular diseases, and bone diseases. Understanding the speciesof PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvementin diverse physiological and pathological processes. In this review, we discuss the structuralcharacteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes.Furthermore, we describe human diseases associated with abnormal expression of LSD1. Thiscomprehensive analysis sheds light on the intricate interplay between PTMs and the functionsof LSD1, highlighting their significance in health and diseases.展开更多
Pluripotent stem cells(PSCs)possess the ability to proliferate indefinitely,self-renew,and differentiate into three germ layers.These pluripotent characteristics allow PSCs to be used to treat many incurable diseases,...Pluripotent stem cells(PSCs)possess the ability to proliferate indefinitely,self-renew,and differentiate into three germ layers.These pluripotent characteristics allow PSCs to be used to treat many incurable diseases,such as spinal cord injury with the embryonic stem cells(ESCs)-derived oligodendrocyte progenitor cells,and dry age-related macular degeneration(AMD)with the ESCs-derived retinal pigment epithelium,and have great application value in clinical regenerative medicine.展开更多
Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein ...Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.展开更多
The functions of the FoxO family proteins,in particular their transcriptional activities,are modulated by post-translational modifi-cations(PTMs),including phosphorylation,acetylation,ubiquitination,methylation and gl...The functions of the FoxO family proteins,in particular their transcriptional activities,are modulated by post-translational modifi-cations(PTMs),including phosphorylation,acetylation,ubiquitination,methylation and glycosylation.These PTMs occur in response to different cellular stresses,which in turn regulate the subcellular localization of FoxO family proteins,as well as their half-life,DNA binding,transcriptional activity and ability to interact with other cellular proteins.In this review,we summarize the role of PTMs of FoxO family proteins in linking their biological and functional relevance with various diseases.展开更多
DNA is highly vulnerable to spontaneous and environmental timely damage in living cells.DNA damage may cause genetic instability and increase cancer risk if the damages are not repaired timely and efficiently.Human ce...DNA is highly vulnerable to spontaneous and environmental timely damage in living cells.DNA damage may cause genetic instability and increase cancer risk if the damages are not repaired timely and efficiently.Human cells possess several DNA damage response(DDR)mechanisms to protect the integrity of their genome.Clarification of the mechanisms under-lying the DNA damage response following lethal damage will facilitate the identification of therapeutic targets for cancers.Histone post-translational modifications(PTMs)have been indicated to play different roles in the repair of DNA damage.In this context,histone PTMs regulate recruitment of downstream effectors,and facilitate appropriate repair response.This review outlines the current understanding of different histone PTMs in response to DNA dam-age repair,besides,enumerates the role of new type PTMs such as histone succinylation and crotonylation in regulating DNA damage repair processes.展开更多
Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the P...Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.展开更多
Hepatocellular carcinoma(HCC)is a common malignant tumor with high incidence and cancer mortality worldwide.Post-translational modifications(PTMs)of proteins have a great impact on protein function.Almost all proteins...Hepatocellular carcinoma(HCC)is a common malignant tumor with high incidence and cancer mortality worldwide.Post-translational modifications(PTMs)of proteins have a great impact on protein function.Almost all proteins can undergo PTMs,including phosphorylation,acetylation,methylation,glycosylation,ubiquitination,and so on.Many studies have shown that PTMs are related to the occurrence and development of cancers.The findings provide novel therapeutic targets for cancers,such as glypican-3 and mucin-1.Other clinical implications are also found in the studies of PTMs.Diagnostic or prognostic value,and response to therapy have been identified.In HCC,it has been shown that glycosylated alpha-fetoprotein(AFP)has a higher detection rate for early liver cancer than conventional AFP.In this review,we mainly focused on the diagnostic and prognostic value of PTM,in order to provide new insights into the clinical implication of PTM in HCC.展开更多
基金supported by grants from the National Key R&D Program of China(2022YFC2403000 and 2021YFC2400500)the National Natural Science Foundation of China(32200728 and 32170925)+3 种基金the Clinical Research Project of Shenzhen Medical Academy of Research and Translation(C2301008)Shenzhen Science and Technology Program(JCYJ20220531100406014,JCYJ2022081800807016,RCBS20221008093336088,KQTD20210811090115019)Guangdong Basic and Applied Basic Research Foundation(2021A1515110375)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210601).
文摘Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.
基金supported by the National Natural Science Foundation of China(32061143005,32170313,and 32100266)Shandong Provincial Natural Science Foundation(ZR2021QC022 and ZR2022QC059).
文摘Protein post-translational modifications(PTMs),such as ubiquitination,phosphorylation,and small ubiquitin-like modifier(SUMO)ylation,are crucial for regulating protein stability,activity,subcellular localization,and binding with cofactors.Such modifications remarkably increase the variety and complexity of proteomes,which are essential for regulating numerous cellular and physiological processes.The regulation of auxin signaling is finely tuned in time and space to guide various plant growth and development.Accumulating evidence indicates that PTMs play critical roles in auxin signaling regulations.Thus,a thorough and systematic review of the functions of PTMs in auxin signal transduction will improve our profound comprehension of the regulation mechanism of auxin signaling and auxin-mediated various processes.This review discusses the progress of protein ubiquitination,phosphorylation,histone acetylation and methylation,SUMOylation,and S-nitrosylation in the regulation of auxin signaling.
文摘Protein-based therapeutics (PPTs) are drugs used to treat a variety of different conditions in the human body by alleviating enzymatic deficiencies, augmenting other proteins and drugs, modulating signal pathways, and more. However, many PPTs struggle from a short half-life due to degradation caused by irreversible protein aggregation in the bloodstream. Currently, the most researched strategies for improving the efficiency and longevity of PPTs are post-translational modifications (PTMs). The goal of our research was to determine which type of PTM increases longevity the most for each of three commonly-used therapeutic proteins by comparing the docking scores (DS) and binding free energies (BFE) from protein aggregation and reception simulations. DS and BFE values were used to create a quantitative index that outputs a relative number from −1 to 1 to show reduced performance, no change, or increased performance. Results showed that methylation was the most beneficial for insulin (p < 0.1) and human growth hormone (p < 0.0001), and both phosphorylation and methylation were somewhat optimal for erythropoietin (p < 0.1 and p < 0.0001, respectively). Acetylation consistently provided the worst benefits with the most negative indices, while methylation had the most positive indices throughout. However, PTM efficacy varied between PPTs, supporting previous studies regarding how each PTM can confer different benefits based on the unique structures of recipient proteins.
基金Supported by Ministerio de Ciencia Innovación y Universidades,No.SAF2017-82436R and SAF2016-75004RComunidad de Madrid,No.S2017/BMD-3686+2 种基金Fundación Ramón Areces,No.2016/CIVP18A3864Instituto de Salud CarlosⅢby Fondos FEDER,No.Cibercv and Ciberehd
文摘The biosynthesis of prostanoids is involved in both physiological and pathological processes.The expression of prostaglandin-endoperoxide synthase 2(PTGS2;also known as COX-2)has been traditionally associated to the onset of several pathologies,from inflammation to cardiovascular,gastrointestinal and oncologic events.For this reason,the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions.In addition to the classic non-steroidal anti-inflammatory drugs,selective and specific PTGS2 inhibitors,termed coxibs,have been generated and widely used.PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1,and it accounts for the elevated prostanoid synthesis that accompanies several pathologies.The main regulation of PTGS2 occurs at the transcription level.In addition to this,the stability of the mRNA is finely regulated through the interaction with several cytoplasmic elements,ranging from specificmicroR NAs to proteins that control mR NA degradation.Moreover,the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation via proteasomal and non-proteasomal mechanisms.Among these modifications,phosphorylation,glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the proinflammatory condition appear to be the main changes.Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress.Finally,these modifications can be used as biomarkers to establish correlations with other parameters,including the immunomodulation dependent on molecular pathological epidemiology determinants,which may provide a better frame for potential therapeutic interventions.
基金This work was supported by the National Natural Science Foundation of China,No.81801210(to SZ).
文摘Deficits in intrinsic neuronal capacities in the spinal cord,a lack of growth support,and suppression of axonal outgrowth by inhibitory molecules mean that spinal cord injury almost always has devastating consequences.As such,one of the primary targets for the treatment of spinal cord injury is to develop strategies to antagonize extrinsic or intrinsic axonal growth-inhibitory factors or enhance the factors that support axonal growth.Among these factors,a series of individual protein level disorders have been identified during the generation of axons following spinal cord injury.Moreover,an increasing number of studies have indicated that post-translational modifications of these proteins have important implications for axonal growth.Some researchers have discovered a variety of post-translational modifications after spinal cord injury,such as tyrosination,acetylation,and phosphorylation.In this review,we reviewed the post-translational modifications for axonal growth,functional recovery,and neuropathic pain after spinal cord injury,a better understanding of which may elucidate the dynamic change of spinal cord injury-related molecules and facilitate the development of a new therapeutic strategy for spinal cord injury.
基金Supported by the “Conselho Nacional de Desenvolvimento Cientifico e Tecnológico”,Grant No.302534/2017-2the “Fundacao de Amparo a Pesquisa do Estado de Sao Paulo”(FAPESP,Grant 2014/21700-3,to JK)
文摘The 57 kDa antigen recognized by the Ki-1 antibody,is also known as intracellular hyaluronic acid binding protein 4 and shares 40.7%identity and 67.4%similarity with serpin mRNA binding protein 1,which is also named CGI-55,or plasminogen activator inhibitor type-1-RNA binding protein-1,indicating that they might be paralog proteins,possibly with similar or redundant functions in human cells.Through the identification of their protein interactomes,both regulatory proteins have been functionally implicated in transcriptional regulation,mRNA metabolism,specifically RNA splicing,the regulation of mRNA stability,especially,in the context of the progesterone hormone response,and the DNA damage response.Both proteins also show a complex pattern of post-translational modifications,involving Ser/Thr phosphorylation,mainly through protein kinase C,arginine methylation and SUMOylation,suggesting that their functions and locations are highly regulated.Furthermore,they show a highly dynamic cellular localization pattern with localizations in both the cytoplasm and nucleus as well as punctuated localizations in both granular cytoplasmic protein bodies,upon stress,and nuclear splicing speckles.Several reports in the literature show altered expressions of both regulatory proteins in a series of cancers as well as mutations in their genes that may contribute to tumorigenesis.This review highlights important aspects of the structure,interactome,post-translational modifications,sub-cellular localization and function of both regulatory proteins and further discusses their possible functions and their potential as tumor markers in different cancer settings.
文摘Mitochondria are essential for cell growth,fission,differentiation,and survival,particularly in undivided cells with high energy requirements,such as cardiomyocytes.The morphology and position of mitochondria change with the activity of mitochondrial fission proteins and mitochondrial fusion proteins.These regulatory mechanisms substan-tially affect cardiomyocyte energy supply and normal function.In mitochondrial fission,dynamin-related protein 1(Drp1)is involved in the separation and degradation of damaged mitochondria,and accurately regulates mitochon-drial renewal and number.Recent studies have revealed a variety of post-translational modification(PTMs)of Drp1,including phosphorylation,SUMOylation,acetylation,O-GlcNAcylation,and S-sulfhydration.These modifications ensure that Drp1 continues to function normally in various signaling pathways,by modulating its activity,stability,and subcellular localization.This article provides an overview of the relationship between Drp1 PTMs and cardiovascular diseases such as heart failure,myocardial infarction,and myocardial ischemia-reperfusion,and describes how these modifications can be targeted and regulated,to help guide cardiovascular disease treatment.
基金supported by grants from the National Natural Science Foundation of China (No.30600197)
文摘Post-translational modifications are rapid, effective and reversible ways to regulate protein stability, localization, function, and their interactions with other molecules. Post-translational modifications usually occur as chemical modifications at amino acid residues, including SUMOylation, phosphorylation, palmitoylation, acetylation, etc. These complex biochemical modifications tightly regulate and control a variety of cellular processes. Several forms of post-translational modifications of huntingtin （Htt） have been described. These modifications affect Htt metabolism, protein-protein interactions and cellular toxicity. Cleavage and clearance of mutant Htt, and the interactions between mutant Htt and other cellular proteins are important biochemical events leading to Huntington＇s disease （HD）. Therefore, identifying signaling pathways of Htt modification and evaluating the significance of Htt modifications would lead to a better understanding of the normal function of wild-type Htt and the pathogenic mechanisms of mutant Htt.
基金Supported by Canadian Institutes of Health Research,Saskatchewan Health Research Foundation,and Natural Sciences and Engineering Research Council of Canada
文摘Replication of hepatitis C virus(HCV)depends on the interaction of viral proteins with various host cellular proteins and signalling pathways.Similar to cellular proteins,post-translational modifications(PTMs)of HCV proteins are essential for proper protein function and regulation,thus,directly affecting viral life cycle and the generation of infectious virus particles.Cleavage of the HCV polyprotein by cellular and viral proteases into more than 10 proteins represents an early protein modification step after translation of the HCV positivestranded RNA genome.The key modifications include the regulated intramembranous proteolytic cleavage of core protein,disulfide bond formation of core,glycosylation of HCV envelope proteins E1 and E2,methylation of nonstructural protein 3(NS3),biotinylation of NS4A,ubiquitination of NS5B and phosphorylation of core and NS5B.Other modifications like ubiquitination of core and palmitoylation of core and NS4B proteins have been reported as well.For some modifications such as phosphorylation of NS3 and NS5A and acetylation of NS3,we have limited understanding of their effects on HCV replication and pathogenesis while the impact of other modifications is far from clear.In this review,we summarize the available information on PTMs of HCV proteins and discuss their relevance to HCV replication and pathogenesis.
文摘Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications(PTMs).PTMs alter the conformation,the stability,the localization,and hence the pattern of interactions of the targeted protein.Cell pathways involve the activation of enzymes,like kinases,ligases and transferases,that,once activated,act on many proteins simultaneously,altering the state of the cell and triggering the processes they are involved in.Viruses enter a balanced system and hijack the cell,exploiting the potential of PTMs either to activate viral encoded proteins or to alter cellular pathways,with the ultimate consequence to perpetuate through their replication.Human T-lymphotropic virus type 1(HTLV-1)is known to be highly oncogenic and associates with adult T-cell leukemia/lymphoma,HTLV-1-associated myelopathy/tropical spastic paraparesis and other inflammatory pathological conditions.HTLV-1 protein activity is controlled by PTMs and,in turn,viral activity is associated with the modulation of cellular pathways based on PTMs.More knowledge is acquired about the PTMs involved in the activation of its proteins,like Tax,Rex,p12,p13,p30,HTLV-I basic leucine zipper factorand Gag.However,more has to be understood at the biochemical level in order to counteract the associated fatal outcomes.This review will focus on known PTMs that directly modify HTLV-1 components and on enzymes whose activity is modulated by viral proteins.
文摘In the present work, computational analyses were applied to study the subcellular localiza-tion and posttranslational modifications of hu-man prion proteins (PrPs). The tentative location of prion protein was determined to be in the nu-cleolus inside the nucleus by the following bio-informatics tools: Hum-PLoc, Euk-PLoc and Nuc-PLoc. Based on our results signal peptides with average of 22 base pairs in N-terminal were identified in human PrPs. This theoretical study demonstrates that PrP is post-translationally modified by: 1) attachment of two N-linked complex carbohydrate moieties (N181 and N197), 2) attachmet of glycosylphosphatidylinositol (GPI) at serine 230 and 3) formation of two di-sulfide bonds between “6–22” and “179–214” cysteines. Furthermore, ten protein kinase phosphorylation sites were predicted in human PrP. The above-noted phosphorylation was car-ried out by PKC and CK2. By using bioinfor-matics tools, we have shown that computation-ally human PrPs locate particularly into the nu-cleolus.
基金supported by National Natural Science Foundation of China(82304047)Sichuan Province Science and Technology Plan Project(2023NSFSC1546,China)+3 种基金Clinical Research Incubation Project of West China Hospital(22HXFH020,China)Cadre Research Health Project of Sichuan Province(2022-116,China)Postdoc project of West China Hospital,Sichuan University and China Postdoctoral Science Foundation(2023HXBH10,2023SCU12067,2022M712246,China)Shanghai Ruizhi Pharmaceutical Technology Co.,Ltd.Broda Research Fund(2023-03,China).
文摘As the most abundant and essential structural protein in the human body,collagen is ubiquitously present in the interstitium of nearly all solid organs,playing a crucial role in maintaining the structural integrity and functional stability of human tissues and organs.Disorders associated with collagen structure and metabolisms impose a significant burden on society and healthcare systems.Posttranslational modifications(PTMs)are essential steps in collagen metabolism,and recent studies have indicated that aberrant regulation of PTMs plays a pivotal role in the pathogenesis and progress of collagen-related disorders,including liver,kidney,heart,lung,and skin fibrosis,as well as keloid.This review provides a comprehensive summary of the regulatory mechanisms of both traditional and novel PTMs in collagen metabolism and collagen-related diseases.Furthermore,we summarize the drugs that modulate PTMs and their effects,with the aim of elucidating the pathophysiology of collagen-related diseases and provide new insights for their diagnosis,prevention,and treatment.
文摘Osteogenesis is driven by the differentiation of osteoblasts and the mineralization of the bone matrix,with oral-derived stem cells playing a significant role in this process.Various post-translational modifications(PTMs),such as phosphorylation,acetylation,methylation,and glycosylation,regulate osteogenic differentiation(OD).These modifications influence the expression of osteogenic genes by modulating the activity of key transcription factors like runt-related transcription factor 2 and osterix.While the molecular mechanisms behind OD are increasingly understood,many questions remain,particularly regarding how PTMs control the specificity and efficiency of stem cell differentiation.Recent research into these modifications has underscored the potential of stem cell therapy for bone regeneration and treating bone-related diseases.This review summarizes the role of PTMs in the OD of oral-derived stem cells,discusses their clinical applications,and suggests future research directions.
基金supported by the Basic Research of Medical Science and Technique Foundation of Henan Province,China(No.SBGJ202301004 to X.B.C.)the Key Project of the High Education from the Education Department of Henan Province,China(No.22ZX008 to Y.C.Z.)+4 种基金the Youth Supporting Program from Henan Province,China(No.2021HYTP060 to Y.C.Z.)the Youth Supporting Program from Zhengzhou University(No.JC202044046 to Y.C.Z.)the Science and Technology Project of Henan Province,China(No.232102311179 to Y.G.)the National Natural Science Foundation of China(No.U21A20416,82020108030 to H.M.L,82103997 to B.W.)the China Postdoctoral Science Foundation(No.2021M692950 to B.W.,2021M702942 to L.J.Z.).
文摘Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine-specific demethylase 1)is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4(H3K4)and histone H3 lysine K9(H3K9).This ability of LSD1 allows it to inhibit or activate transcription.LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of thesePTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders,neurological disorders, cardiovascular diseases, and bone diseases. Understanding the speciesof PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvementin diverse physiological and pathological processes. In this review, we discuss the structuralcharacteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes.Furthermore, we describe human diseases associated with abnormal expression of LSD1. Thiscomprehensive analysis sheds light on the intricate interplay between PTMs and the functionsof LSD1, highlighting their significance in health and diseases.
基金supported by the National Key Research and Development Program of China(2024YFA0916400)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0480000)+5 种基金the National Natural Science Foundation of China(32025010,32488301,92254301,92357302,92157202,32241002,32261160376,32322022,and 32471358)Major Project of Guangzhou National Laboratory(GZNL2024A03006 and GZNL2024B01003)the Key Research Program,CAS(ZDBS-ZRKJZ-TLC003,YSBR-075 and 188GJHZ2024048GC)Guangdong Province Science and Technology Program(2023B0303000023,2023B1111050005,2023B1212060050,2023B1212120009,2024B1515040020,and 2024A1515010782)Guangzhou Science and Technology Program(202206060002 and 2025A04J7110)Health@InnoHK funding support from the Innovation Technology Commission of the Hong Kong SAR,and Major Research Project(GIBHMRP25-01)Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences.
文摘Pluripotent stem cells(PSCs)possess the ability to proliferate indefinitely,self-renew,and differentiate into three germ layers.These pluripotent characteristics allow PSCs to be used to treat many incurable diseases,such as spinal cord injury with the embryonic stem cells(ESCs)-derived oligodendrocyte progenitor cells,and dry age-related macular degeneration(AMD)with the ESCs-derived retinal pigment epithelium,and have great application value in clinical regenerative medicine.
基金supported by Applied Basic Research Joint Fund Project of Yunnan Province,No.202301AY070001-200Middle-aged Academic and Technical Training Project for High-Level Talents,No.202105AC160065+1 种基金Yunnan Clinical Medical Center for Neurological and Cardiovascular Diseases,No.YWLCYXZX2023300077Key Clinical Specialty of Neurology in Yunnan Province,No.300064(all to CL)。
文摘Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.
基金supported by the grants from the Ministry of Science and Technology of China (Grant 2011CB910100)the National Natural Science Foundation of China (Grants 30900722 and 31070691).
文摘The functions of the FoxO family proteins,in particular their transcriptional activities,are modulated by post-translational modifi-cations(PTMs),including phosphorylation,acetylation,ubiquitination,methylation and glycosylation.These PTMs occur in response to different cellular stresses,which in turn regulate the subcellular localization of FoxO family proteins,as well as their half-life,DNA binding,transcriptional activity and ability to interact with other cellular proteins.In this review,we summarize the role of PTMs of FoxO family proteins in linking their biological and functional relevance with various diseases.
基金supported by National Natural Science Foundation of China(No.82071695,82060535)Natural Science Foundation of Gansu Province,China(No.21JR7RA450)。
文摘DNA is highly vulnerable to spontaneous and environmental timely damage in living cells.DNA damage may cause genetic instability and increase cancer risk if the damages are not repaired timely and efficiently.Human cells possess several DNA damage response(DDR)mechanisms to protect the integrity of their genome.Clarification of the mechanisms under-lying the DNA damage response following lethal damage will facilitate the identification of therapeutic targets for cancers.Histone post-translational modifications(PTMs)have been indicated to play different roles in the repair of DNA damage.In this context,histone PTMs regulate recruitment of downstream effectors,and facilitate appropriate repair response.This review outlines the current understanding of different histone PTMs in response to DNA dam-age repair,besides,enumerates the role of new type PTMs such as histone succinylation and crotonylation in regulating DNA damage repair processes.
基金This work was supported by the National Natural Science Foundation of China(81622005)Beijing Natural Science Foundation(7172213).
文摘Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.
基金funded by National Natural Science Foundation of China(81772982)the Special Innovation Fund of Department of Education of Guangdong Province(2019KTSCX049)+1 种基金Discipline Construction Project of Guang-dong Medical University(4SG23034G)Talent Development Foundation of The First Dongguan Affiliated Hospital of Guangdong Medical University(PF100-2-03).
文摘Hepatocellular carcinoma(HCC)is a common malignant tumor with high incidence and cancer mortality worldwide.Post-translational modifications(PTMs)of proteins have a great impact on protein function.Almost all proteins can undergo PTMs,including phosphorylation,acetylation,methylation,glycosylation,ubiquitination,and so on.Many studies have shown that PTMs are related to the occurrence and development of cancers.The findings provide novel therapeutic targets for cancers,such as glypican-3 and mucin-1.Other clinical implications are also found in the studies of PTMs.Diagnostic or prognostic value,and response to therapy have been identified.In HCC,it has been shown that glycosylated alpha-fetoprotein(AFP)has a higher detection rate for early liver cancer than conventional AFP.In this review,we mainly focused on the diagnostic and prognostic value of PTM,in order to provide new insights into the clinical implication of PTM in HCC.
