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
It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular ...It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain.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
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
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
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
Post-translational modifications（PTMs） occurring at protein lysine residues,or protein lysine modifications（PLMs）,play critical roles in regulating biological processes.Due to the explosive expansion of the amount...Post-translational modifications（PTMs） occurring at protein lysine residues,or protein lysine modifications（PLMs）,play critical roles in regulating biological processes.Due to the explosive expansion of the amount of PLM substrates and the discovery of novel PLM types,here we greatly updated our previous studies,and presented a much more integrative resource of protein lysine modification database（PLMD）.In PLMD,we totally collected and integrated 284,780 modification events in 53,501 proteins across 176 eukaryotes and prokaryotes for up to 20 types of PLMs,including ubiquitination, acetylation, sumoylation, methylation ,succinylation,malonylation,glutarylation,giycation,formylation,hydroxylation,butyrylation,propionylation,crotonylation,pupylation,neddylation,2-hydroxyisobutyrylation,phosphoglycerylation,carboxylation,lipoylation and biotinylation.Using the data set,a motif-based analysis was performed for each PLM type,and the results demonstrated that different PLM types preferentially recognize distinct sequence motifs for the modifications.Moreover,various PLMs synergistically orchestrate specific cellular biological processes by mutual crosstalks with each other,and we totally found 65,297 PLM events involved in 90 types of PLM co-occurrences on the same lysine residues.Finally,various options were provided for accessing the data,while original references and other annotations were also present for each PLM substrate.Taken together,we anticipated the PLMD database can serve as a useful resource for further researches of PLMs.PLMD 3.0 was implemented in PHP ＋ MySQL and freely available at http：//plmd.biocuckoo.org.展开更多
The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain f...The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear.This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation.We conducted succinylome analysis of hippocampal proteins in germ-free(GF)and specific pathogen-free(SPF)mice and metagenomic analysis of feces from SPF mice.These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice.Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins,including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice.We constructed a panoramic map of gut microbiota-regulated succinylation,acetylation,and phosphorylation,and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways.Pearson correlation analysis indicated that 13 taxa,predominantly belonging to the Bacteroidetes phylum,were correlated with the biological functions of post-translational modifications.Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways.This study highlights the hippocampal physiological changes induced by the absence of gut microbiota,and proteomic quantification of succinylation,phosphorylation,and acetylation,contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.展开更多
Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of pro...Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.展开更多
This study investigated the integrated atlas of protein phosphorylation,acetylation,ubiquitination and S-nitrosylation in pre-rigor(0.5 h)and post-rigor(5 days)lamb to interpret the roles of protein posttranslational ...This study investigated the integrated atlas of protein phosphorylation,acetylation,ubiquitination and S-nitrosylation in pre-rigor(0.5 h)and post-rigor(5 days)lamb to interpret the roles of protein posttranslational modifications(PTMs)during meat aging.The results showed that the most common PTMs in postmortem meat were phosphorylated proteins.PTMs regulation during the postmortem period altered proteins involved in metabolic pathways and muscle contraction.The phosphorylation and ubiquitination of proteins located in mitochondria and nuclear changed significantly between 0.5 h and 5 days postmortem.Gene set enrichment analysis revealed possible roles of total PTMs proteins,with a general downregulation of phosphorylation,acetylation and ubiquitination.There was a weak correlation in the lysine PTM of acetylation and ubiquitination at the same site in postmortem meat.Multiple PTMs of proteins in glycolysis,TCA cycle,muscle contraction and the calcium signaling pathway cooperatively regulate meat quality development from pre-rigor to post-rigor.展开更多
Post-translational modifications(PTMs)play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality.PTMs involve the covalent attachment of distinct chemical groups,such as suc...Post-translational modifications(PTMs)play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality.PTMs involve the covalent attachment of distinct chemical groups,such as succinyl,crotonyl,and lactyl,at specific protein sites,which alter protein structure,function,stability,and activity,ultimately influencing biological processes.Recently,metabolically derived short-chain acylation modifications(with acyl groups containing fewer than six carbon atoms)have been progressively identified,such as butyrylation,succinylation,crotonylation,and lactylation,differing from traditional acetylation in structure,physicochemical properties,function,and regulation.Aberrant short-chain acyl-PTMs are often associated with tumorigenesis.Research highlights that PTMs like succinylation and lactylation are essential in regulating tumor metabolism,drug resistance,and immune responses.This review elucidates the regulatory mechanisms of eight short-chain acyl-PTMs—butyrylation,succinylation,crotonylation,malonylation,glutarylation,2-hydroxyisobutyrylation,β-hydroxybutyrylation,and lactylation—that are involved in tumor initiation and progression.Their roles in controlling tumor genomic stability,gene transcription,protein stability,enzyme activity,and nuclear localization are summarized,demonstrating their impact on related biological processes such as tumor metabolism,multi-drug resistance,and immune evasion.Additionally,the review provides an overview of current drug research targeting enzymes that regulate PTMs,offering critical insights to advance therapeutic strategies for cancer treatment.展开更多
Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcr...Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcription,translation,DNA damage repair etc.,and it is upregulated during times of environmental stress.YBX1 is localized in both the cytoplasm and the nucleus.There,its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression.Additionally,YBX1 expression is upregulated in a variety of cancers,pointing towards its role as a potential oncogene.Under certain circumstances,YBX1 also promotes the expression of multidrug resistance 1(MDR1)gene,which is involved in the development of drug resistance.Thus,it is critical to understand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development.A number of recent studies have highlighted the mechanisms of YBX1 regulation.Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function.Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently,S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth.This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1.This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation,which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.展开更多
Lysine succinylation(Ksuc)is a novel protein post-translational modification(PTM)wherein a succinyl group modifies a lysine residue.Ksuc leads to significant chemical and struc-tural changes to the modified protein.Re...Lysine succinylation(Ksuc)is a novel protein post-translational modification(PTM)wherein a succinyl group modifies a lysine residue.Ksuc leads to significant chemical and struc-tural changes to the modified protein.Recent studies have shown that Ksuc might play an important role in organism physiology and some pathophysiological processes,such as tumor-igenesis and metabolic diseases.To provide an understanding of the molecular mechanism and functions of Ksuc in different organisms,we reviewed the current literature about Ksuc,mainly summarizing the research advances in eukaryotes and prokaryotes based on both traditional study methods and site prediction tools.We also discussed inhibitors or activators associated with Ksuc that may contribute to proteomic studies and could be useful in future clinical prac-tice.A deeper understanding of Ksuc may shed new light on life science at the protein level and could lead to novel therapeutic strategies for various diseases.展开更多
The devastating coronavirus disease 2019(COVID-19)pandemic has prompted worldwide efforts to study structural biological traits of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its viral components.Co...The devastating coronavirus disease 2019(COVID-19)pandemic has prompted worldwide efforts to study structural biological traits of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its viral components.Compared to the Spike protein,which is the primary target for currently available vaccines or antibodies,knowledge about other virion structural components is incomplete.Using high-resolution mass spectrometry,we report a comprehensive post-translational modification(PTM)analysis of nucleocapsid phosphoprotein(NCP),the most abundant structural component of the SARS-CoV-2 virion.In addition to phosphoryl groups,we show that the SARS-CoV-2 NCP is decorated with a variety of PTMs,including N-glycans and ubiquitin.Based on newly identified PTMs,refined protein structural models of SARS-CoV-2 NCP were proposed and potential immune recognition epitopes of NCP were aligned with PTMs.These data can facilitate the design of novel vaccines or therapeutics targeting NCP,as valuable alternatives to the current vaccination and treatment paradigm that is under threat of the ever-mutating SARS-CoV-2 Spike protein.展开更多
Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophos...Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophosphate-activated protein kinase(AMPK)succinylation in cholelithiasis.Using mouse models and gallbladder mucosal epithelial cells,they found that KAT2A inhibits gallstones through AMPK K170 succinylation,thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis.This study is the first to connect lysine succinylation with cholelithiasis,offering new insights and identifying succinylation as a potential therapeutic target.Future research should confirm these findings using patient samples,investigate other posttranslational modifications,and use structural biology to clarify succinylationinduced conformational changes,thereby bridging basic research to clinical applications.展开更多
Protein phosphorylation,one of the major post-translational modifications,plays a crucial role in cell signaling,DNA replication,gene expression and differentiation;and alters enzyme activity and other biological acti...Protein phosphorylation,one of the major post-translational modifications,plays a crucial role in cell signaling,DNA replication,gene expression and differentiation;and alters enzyme activity and other biological activities;and regulates cell proliferation and enlargement,phytohormone biosynthesis and signaling,plant disease resistance,and grain filling and quality during rice seed development.Research work on protein phosphorylation started in the 1950 s with the discovery of phosphorylase a and phosphorylase b which are phospho and dephospho forms of the same enzyme.Over the last decade,rice proteomics has accomplished tremendous progress in setting up techniques to proteome nearly all tissues,organs and organelles.The progress made in this field is evident in number of research works.However,research on rice protein phosphorylation is still at its infancy and there are still many unanswered questions.In this review,the general description of protein phosphorylation,including history,structure,frequency of occurrence and function,are discussed.This work also elucidates the different methods for identification,qualification and finally,the progress in rice phosphoproteome research and perspectives.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
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
The liver is the site of synthesis of the majority of circulating proteins.Besides initial polypeptide synthesis,sophisticated machinery is involved in the further processing of proteins by removing parts of them and/...The liver is the site of synthesis of the majority of circulating proteins.Besides initial polypeptide synthesis,sophisticated machinery is involved in the further processing of proteins by removing parts of them and/or adding functional groups and small molecules tailoring the final molecule to suit its physiological purpose.Posttranslational modifications(PTMs)design a network of molecules with the common protein ancestor but with slightly or considerably varying activity/localization/purpose.PTMs can change under pathological conditions,giving rise to aberrant or overmodified proteins.Undesired changes in the structure of proteins most often accompany undesired changes in their function,such as reduced activity or the appearance of new effects.Proper protein processing is essential for the reactions in living beings and crucial for the overall quality control.Modifications that occur on proteins synthesized in the liver whose PTMs are cirrhosis-related are oxidation,nitration,glycosylation,acetylation,and ubiquitination.Some of them predominantly affect proteins that remain in liver cells,whereas others predominantly occur on proteins that leave the liver or originate from other tissues and perform their function in the circulation.Altered PTMs of certain proteins are potential candidates as biomarkers of liver-related diseases,including cirrhosis.This review will focus on PTMs on proteins whose structural changes in cirrhosis exert or are suspected to exert the most serious functional consequences.展开更多
MicroRNAs （miRNAs） post-transcriptionally regulate gene expression by binding to target mRNAs with perfect or imperfect complementarity, recruiting an Argonaute （AGO） protein complex that usually results in degrad...MicroRNAs （miRNAs） post-transcriptionally regulate gene expression by binding to target mRNAs with perfect or imperfect complementarity, recruiting an Argonaute （AGO） protein complex that usually results in degradation or translational repression of the target mRNA. AGO proteins function as the Slicer enzyme in miRNA and small interfering RNA （siRNA） pathways involved in human physiological and pathophysiological processes, such as antiviral responses and disease formation. Although the past decade has witnessed rapid advancement in studies of AGO protein functions, to further elucidate the molecular mechanism of AGO proteins in cellular function and biochemical process is really a challenging area for researchers. In order to understand the molecular causes underlying the pathological processes, we mainly focus on five fundamental problems of AGO proteins, including evolution, functional domain, subcellular location, post-translational modification and protein-protein interactions. Our discussion highlight their roles in early diagnosis, disease prevention, drug target identification, drug response, etc.展开更多
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It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain.
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.
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.
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 grants from the National Basic Research Program(973 projectNo.2013CB933900)+1 种基金the Natural Science Foundation of China(Nos.31671360 andJ1103514)the International Science & Technology Cooperation Program of China (No.2014DFB30020)
文摘Post-translational modifications（PTMs） occurring at protein lysine residues,or protein lysine modifications（PLMs）,play critical roles in regulating biological processes.Due to the explosive expansion of the amount of PLM substrates and the discovery of novel PLM types,here we greatly updated our previous studies,and presented a much more integrative resource of protein lysine modification database（PLMD）.In PLMD,we totally collected and integrated 284,780 modification events in 53,501 proteins across 176 eukaryotes and prokaryotes for up to 20 types of PLMs,including ubiquitination, acetylation, sumoylation, methylation ,succinylation,malonylation,glutarylation,giycation,formylation,hydroxylation,butyrylation,propionylation,crotonylation,pupylation,neddylation,2-hydroxyisobutyrylation,phosphoglycerylation,carboxylation,lipoylation and biotinylation.Using the data set,a motif-based analysis was performed for each PLM type,and the results demonstrated that different PLM types preferentially recognize distinct sequence motifs for the modifications.Moreover,various PLMs synergistically orchestrate specific cellular biological processes by mutual crosstalks with each other,and we totally found 65,297 PLM events involved in 90 types of PLM co-occurrences on the same lysine residues.Finally,various options were provided for accessing the data,while original references and other annotations were also present for each PLM substrate.Taken together,we anticipated the PLMD database can serve as a useful resource for further researches of PLMs.PLMD 3.0 was implemented in PHP ＋ MySQL and freely available at http：//plmd.biocuckoo.org.
基金supported by the Natural Science Foundation Project of China(81820108015,82201683)China Postdoctoral Science Foundation(2021M693926,2020TQ0393,2020M683634XB)+1 种基金Chongqing Science&Technology Commission(cstc2021jcyj-bshX0150,cstc2021jcyj-bshX0201)Special Funding for Chongqing Postdoctoral Research Projects(2021XMT001)。
文摘The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear.This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation.We conducted succinylome analysis of hippocampal proteins in germ-free(GF)and specific pathogen-free(SPF)mice and metagenomic analysis of feces from SPF mice.These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice.Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins,including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice.We constructed a panoramic map of gut microbiota-regulated succinylation,acetylation,and phosphorylation,and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways.Pearson correlation analysis indicated that 13 taxa,predominantly belonging to the Bacteroidetes phylum,were correlated with the biological functions of post-translational modifications.Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways.This study highlights the hippocampal physiological changes induced by the absence of gut microbiota,and proteomic quantification of succinylation,phosphorylation,and acetylation,contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.
基金supported by the Natural Science Foundation of Guangdong Province(No.2024A1515010605,2022A1515140034)Discipline Construction Project of Guangdong Medical University(No.4SG24007G,4SG22302P)+1 种基金Medical Scientific Research Fund of Guangdong Province(No.B2024193)Dongguan Social Development and Scientific Technology Project,China(No.20231800936562).
文摘Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.
基金the financial support from the General and Key Programs of the National Natural Science Foundation of China(32072288,32030086)Central Public-interest Scientific Institution Basal Research Fund(S2019RCJC01)。
文摘This study investigated the integrated atlas of protein phosphorylation,acetylation,ubiquitination and S-nitrosylation in pre-rigor(0.5 h)and post-rigor(5 days)lamb to interpret the roles of protein posttranslational modifications(PTMs)during meat aging.The results showed that the most common PTMs in postmortem meat were phosphorylated proteins.PTMs regulation during the postmortem period altered proteins involved in metabolic pathways and muscle contraction.The phosphorylation and ubiquitination of proteins located in mitochondria and nuclear changed significantly between 0.5 h and 5 days postmortem.Gene set enrichment analysis revealed possible roles of total PTMs proteins,with a general downregulation of phosphorylation,acetylation and ubiquitination.There was a weak correlation in the lysine PTM of acetylation and ubiquitination at the same site in postmortem meat.Multiple PTMs of proteins in glycolysis,TCA cycle,muscle contraction and the calcium signaling pathway cooperatively regulate meat quality development from pre-rigor to post-rigor.
基金National Natural Science Foundation of China,Grant/Award Number:82272915Science and Technology Innovation Team Project of China Medical University,Grant/Award Number:CXTD2022007+3 种基金Beijing Xisike Clinical Oncology Research Foundation,Grant/Award Number:Y-Gilead2024-PT-0201China Postdoctoral Science Foundation,Grant/Award Numbers:2023MD734246,2025T180577Liaoning Province Natural Science Foundation Joint Fund,Grant/Award Number:2023-MSLH-396Doctoral Start-up Foundation of Liaoning Province,Grant/Award Number:2024-BS-066。
文摘Post-translational modifications(PTMs)play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality.PTMs involve the covalent attachment of distinct chemical groups,such as succinyl,crotonyl,and lactyl,at specific protein sites,which alter protein structure,function,stability,and activity,ultimately influencing biological processes.Recently,metabolically derived short-chain acylation modifications(with acyl groups containing fewer than six carbon atoms)have been progressively identified,such as butyrylation,succinylation,crotonylation,and lactylation,differing from traditional acetylation in structure,physicochemical properties,function,and regulation.Aberrant short-chain acyl-PTMs are often associated with tumorigenesis.Research highlights that PTMs like succinylation and lactylation are essential in regulating tumor metabolism,drug resistance,and immune responses.This review elucidates the regulatory mechanisms of eight short-chain acyl-PTMs—butyrylation,succinylation,crotonylation,malonylation,glutarylation,2-hydroxyisobutyrylation,β-hydroxybutyrylation,and lactylation—that are involved in tumor initiation and progression.Their roles in controlling tumor genomic stability,gene transcription,protein stability,enzyme activity,and nuclear localization are summarized,demonstrating their impact on related biological processes such as tumor metabolism,multi-drug resistance,and immune evasion.Additionally,the review provides an overview of current drug research targeting enzymes that regulate PTMs,offering critical insights to advance therapeutic strategies for cancer treatment.
基金This research is supported by grants 4186265(American Cancer Society)and 23-862-07 and 036433730102(Indiana University)to TL.
文摘Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcription,translation,DNA damage repair etc.,and it is upregulated during times of environmental stress.YBX1 is localized in both the cytoplasm and the nucleus.There,its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression.Additionally,YBX1 expression is upregulated in a variety of cancers,pointing towards its role as a potential oncogene.Under certain circumstances,YBX1 also promotes the expression of multidrug resistance 1(MDR1)gene,which is involved in the development of drug resistance.Thus,it is critical to understand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development.A number of recent studies have highlighted the mechanisms of YBX1 regulation.Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function.Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently,S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth.This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1.This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation,which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.
基金supported by National Natural Science Foundation of China(No.82002172)Key Scientific Research Project Plan of Henan Province(No.20A180001)Innovation program of Henan university students(No.202110475033,20217003003).
文摘Lysine succinylation(Ksuc)is a novel protein post-translational modification(PTM)wherein a succinyl group modifies a lysine residue.Ksuc leads to significant chemical and struc-tural changes to the modified protein.Recent studies have shown that Ksuc might play an important role in organism physiology and some pathophysiological processes,such as tumor-igenesis and metabolic diseases.To provide an understanding of the molecular mechanism and functions of Ksuc in different organisms,we reviewed the current literature about Ksuc,mainly summarizing the research advances in eukaryotes and prokaryotes based on both traditional study methods and site prediction tools.We also discussed inhibitors or activators associated with Ksuc that may contribute to proteomic studies and could be useful in future clinical prac-tice.A deeper understanding of Ksuc may shed new light on life science at the protein level and could lead to novel therapeutic strategies for various diseases.
基金supported by the National Natural Science Foundation of China(U20A20343)the National Key Research and Development Program(2017YFC1200204)+1 种基金Emergency Project of Zhejiang Provincial Department of Science and Technology(2020C03123-1)Fundamental Research Funds for the Central Universities(2018XZZX001-13).
文摘The devastating coronavirus disease 2019(COVID-19)pandemic has prompted worldwide efforts to study structural biological traits of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its viral components.Compared to the Spike protein,which is the primary target for currently available vaccines or antibodies,knowledge about other virion structural components is incomplete.Using high-resolution mass spectrometry,we report a comprehensive post-translational modification(PTM)analysis of nucleocapsid phosphoprotein(NCP),the most abundant structural component of the SARS-CoV-2 virion.In addition to phosphoryl groups,we show that the SARS-CoV-2 NCP is decorated with a variety of PTMs,including N-glycans and ubiquitin.Based on newly identified PTMs,refined protein structural models of SARS-CoV-2 NCP were proposed and potential immune recognition epitopes of NCP were aligned with PTMs.These data can facilitate the design of novel vaccines or therapeutics targeting NCP,as valuable alternatives to the current vaccination and treatment paradigm that is under threat of the ever-mutating SARS-CoV-2 Spike protein.
基金Supported by Wenzhou Science and Technology Bureau,No.Y20240207.
文摘Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophosphate-activated protein kinase(AMPK)succinylation in cholelithiasis.Using mouse models and gallbladder mucosal epithelial cells,they found that KAT2A inhibits gallstones through AMPK K170 succinylation,thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis.This study is the first to connect lysine succinylation with cholelithiasis,offering new insights and identifying succinylation as a potential therapeutic target.Future research should confirm these findings using patient samples,investigate other posttranslational modifications,and use structural biology to clarify succinylationinduced conformational changes,thereby bridging basic research to clinical applications.
文摘Protein phosphorylation,one of the major post-translational modifications,plays a crucial role in cell signaling,DNA replication,gene expression and differentiation;and alters enzyme activity and other biological activities;and regulates cell proliferation and enlargement,phytohormone biosynthesis and signaling,plant disease resistance,and grain filling and quality during rice seed development.Research work on protein phosphorylation started in the 1950 s with the discovery of phosphorylase a and phosphorylase b which are phospho and dephospho forms of the same enzyme.Over the last decade,rice proteomics has accomplished tremendous progress in setting up techniques to proteome nearly all tissues,organs and organelles.The progress made in this field is evident in number of research works.However,research on rice protein phosphorylation is still at its infancy and there are still many unanswered questions.In this review,the general description of protein phosphorylation,including history,structure,frequency of occurrence and function,are discussed.This work also elucidates the different methods for identification,qualification and finally,the progress in rice phosphoproteome research and perspectives.
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).
基金Supported by the Ministry of Education,Science and Technological Development of the Republic of Serbia,No.451-03-9/2021-14/200019.
文摘The liver is the site of synthesis of the majority of circulating proteins.Besides initial polypeptide synthesis,sophisticated machinery is involved in the further processing of proteins by removing parts of them and/or adding functional groups and small molecules tailoring the final molecule to suit its physiological purpose.Posttranslational modifications(PTMs)design a network of molecules with the common protein ancestor but with slightly or considerably varying activity/localization/purpose.PTMs can change under pathological conditions,giving rise to aberrant or overmodified proteins.Undesired changes in the structure of proteins most often accompany undesired changes in their function,such as reduced activity or the appearance of new effects.Proper protein processing is essential for the reactions in living beings and crucial for the overall quality control.Modifications that occur on proteins synthesized in the liver whose PTMs are cirrhosis-related are oxidation,nitration,glycosylation,acetylation,and ubiquitination.Some of them predominantly affect proteins that remain in liver cells,whereas others predominantly occur on proteins that leave the liver or originate from other tissues and perform their function in the circulation.Altered PTMs of certain proteins are potential candidates as biomarkers of liver-related diseases,including cirrhosis.This review will focus on PTMs on proteins whose structural changes in cirrhosis exert or are suspected to exert the most serious functional consequences.
文摘MicroRNAs （miRNAs） post-transcriptionally regulate gene expression by binding to target mRNAs with perfect or imperfect complementarity, recruiting an Argonaute （AGO） protein complex that usually results in degradation or translational repression of the target mRNA. AGO proteins function as the Slicer enzyme in miRNA and small interfering RNA （siRNA） pathways involved in human physiological and pathophysiological processes, such as antiviral responses and disease formation. Although the past decade has witnessed rapid advancement in studies of AGO protein functions, to further elucidate the molecular mechanism of AGO proteins in cellular function and biochemical process is really a challenging area for researchers. In order to understand the molecular causes underlying the pathological processes, we mainly focus on five fundamental problems of AGO proteins, including evolution, functional domain, subcellular location, post-translational modification and protein-protein interactions. Our discussion highlight their roles in early diagnosis, disease prevention, drug target identification, drug response, etc.
