Prostate cancer(PCa)is the most commonly diagnosed cancer among men in western countries.Androgen receptor(AR)signaling plays key roles in the development of PCa.Androgen deprivation therapy(ADT)remains the standard t...Prostate cancer(PCa)is the most commonly diagnosed cancer among men in western countries.Androgen receptor(AR)signaling plays key roles in the development of PCa.Androgen deprivation therapy(ADT)remains the standard therapy for advanced PCa.In addition to its ligand androgen,accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa,especially in castration resistant prostate cancer(CRPC).To date,a number of posttranscriptional modifications of AR have been identified,including phosphorylation(e.g.by CDK1),acetylation(e.g.by p300 and recognized by BRD4),methylation(e.g.by EZH2),ubiquitination(e.g.by SPOP),and SUMOylation(e.g.by PIAS1).These modifications are essential for the maintenance of protein stability,nuclear localization and transcriptional activity of AR.This review summarizes posttranslational modifications that influence androgen-dependent and-independent activities of AR,PCa progression and therapy resistance.We further emphasize that in addition to androgen,posttranslational modification is another important way to regulate AR activity,suggesting that targeting AR posttranslational modifications,such as proteolysis targeting chimeras(PROTACs)of AR,represents a potential and promising alternate for effective treatment of CRPC.Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.展开更多
Posttranslational modifications are a class of important cellular activities in various bio-chemical processes including signalling trans-duction, gene/metabolite networks, and disease development. It has been found t...Posttranslational modifications are a class of important cellular activities in various bio-chemical processes including signalling trans-duction, gene/metabolite networks, and disease development. It has been found that multiple posttranslational modifications with the same or different modification residues can co-exist in the same protein and this co-occurrence is critical to signalling networks in cells. Although some biological studies have spotted this phe-nomenon, little bioinformatics study has been carried out for understanding its mechanism. Four data sets were downloaded from NCBI for the study. The joint probabilities of any two neighbouring posttranslational modification sites of different modification residues were analyzed. The Bayesian probabilistic network was derived for visualizing the relationship be-tween a target modification and the contributing modifications as the predictive factors.展开更多
In a recent article published in Cell,He and colleagues reported that vitamin C(VitC)modifies lysine residues in proteins and peptides,thereby forming vitcyl-lysine,a process they have called vitcylation.They show tha...In a recent article published in Cell,He and colleagues reported that vitamin C(VitC)modifies lysine residues in proteins and peptides,thereby forming vitcyl-lysine,a process they have called vitcylation.They show that vitcylation of signal transducer and activator of transcription-1(STAT1)increases its phosphorylation and thereby promotes interferon pathway activation in cancer cells and anti-tumor immunity.展开更多
The NLRP3 inflammasome functions as an inflammatory driver,but its relationship with lipid metabolic changes in early sepsis remains unclear.Here,we found that GITR expression in monocytes/macrophages was induced by l...The NLRP3 inflammasome functions as an inflammatory driver,but its relationship with lipid metabolic changes in early sepsis remains unclear.Here,we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine(LPC)and was positively correlated with the severity of sepsis.GITR is a costimulatory molecule that is mainly expressed on T cells,but its function in macrophages is largely unknown.Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis.Furthermore,in vivo studies using either cecal ligation and puncture(CLP)or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality,while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1βdeficiency attenuated sepsis severity/lethality.Mechanistically,GITR specifically enhanced inflammasome activation by regulating the posttranslational modification(PTM)of NLRP3.GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation,leading to decreasing ubiquitination but increasing acetylation of NLRP3.Overall,these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury,suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases.展开更多
Intermediate filaments(IFs)in human cells are the products of six distinct gene families,all sharing homology in a core rod domain.These IFs assemble into non-polar polymers,providing cytoplasmic and nuclear mechanica...Intermediate filaments(IFs)in human cells are the products of six distinct gene families,all sharing homology in a core rod domain.These IFs assemble into non-polar polymers,providing cytoplasmic and nuclear mechanical support.Recent research has revealed the active and dynamic properties of IFs and their binding partners.This regulation extends beyond cell mechanics to include migration,mechanotransduction,and tumor growth.Therefore,this comprehensive review aims to catalog all human IF genes and IF-associated proteins(IFAPs),detailing their names,sizes,functions,associated human diseases,relevant literature,and links to resources like UniProt and the Protein Atlas database.These links provide access to additional information such as protein structure,subcellular localization,disease-causing mutations,and pathology.Using this catalog,we will provide an overview of the current understanding of the biological functions of IFs and IFAPs.This overview is crucial for identifying gaps in their characterization and understanding IF-mediated mechanotransduction.Additionally,we will consider potential future research directions.展开更多
Altered metabolism is a hallmark of cancer,and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors.It is well recognized that long noncoding RNAs(lncRNAs)regulate ene...Altered metabolism is a hallmark of cancer,and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors.It is well recognized that long noncoding RNAs(lncRNAs)regulate energy metabolism in cancer.However,lncRNA-mediated posttranslational modifications and metabolic reprogramming are unclear at present.In this review,we summarized the current understanding of the interactions between the alterations in cancer-associated energy metabolism and the lncRNA-mediated posttranslational modifications of metabolic enzymes,transcription factors,and other proteins involved in metabolic pathways.In addition,we discuss the mechanisms through which these interactions contribute to tumor initiation and progression,and the key roles and clinical significance of functional lncRNAs.We believe that an in-depth understanding of lncRNA-mediated cancer metabolic reprogramming can help to identify cellular vulnerabilities that can be exploited for cancer diagnosis and therapy.展开更多
Legionella pneumophila is a Gram-negative bacterium ubiquitously present in freshwater environments and causes a serious type of pneumonia called Legionnaires’disease.During infections,L.pneumophila releases over 300...Legionella pneumophila is a Gram-negative bacterium ubiquitously present in freshwater environments and causes a serious type of pneumonia called Legionnaires’disease.During infections,L.pneumophila releases over 300 effector proteins into host cells through an Icm/Dot type IV secretion system to manipulate the host defense system for survival within the host.Notably,certain effector proteins mediate posttranslational modifications(PTMs),serving as useful approaches exploited by L.pneumophila to modify host proteins.Some effectors catalyze the addition of host protein PTMs,while others mediate the removal of PTMs from host proteins.In this review,we summarize L.pneumophila effector-mediated PTMs of host proteins,including phosphorylation,ubiquitination,glycosylation,AMPylation,phosphocholination,methylation,and ADP-ribosylation,as well as dephosphorylation,deubiquitination,deAMPylation,deADP-ribosylation,dephosphocholination,and delipidation.We describe their molecular mechanisms and biological functions in the regulation of bacterial growth and Legionella-containing vacuole biosynthesis and in the disruption of host immune and defense machinery.展开更多
Glyceraldehyde-3-phosphate dehydrogenase （GAPDH）, initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. H...Glyceraldehyde-3-phosphate dehydrogenase （GAPDH）, initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and pnsttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 （HIF-1）, p53, nitric oxide （NO）, and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications （PTMs） occurring in GAPDH in cancer cells result in new activities unrelated to the original glycnlytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described.展开更多
The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation ...The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation to ensure its proper function. Defects in PTEN regulation have a profound impact on carcinogenesis. In this review, we briefly discuss recent advances concerning PTEN regulation and how such knowledge facilitates our understanding and further exploration of PTEN biology. The carboxyl-tail of PTEN, which appears to be associated with multiple types of posttranslational regulation, will be under detailed scrutiny. Further, a comparative analysis of PTEN and p53 suggests while p53 needs to be activated to suppress tumorigenesis （a dormant gatekeeper）, PTEN is probably a constitutive surveillant against cancer development, thus a default gatekeeper.展开更多
Leptospirosis is a widespread zoonotic disease caused by pathogenic spirochetes of the genus Leptospira that infects humans and a wide range of animals. By combining computational prediction and high-accuracy tandem m...Leptospirosis is a widespread zoonotic disease caused by pathogenic spirochetes of the genus Leptospira that infects humans and a wide range of animals. By combining computational prediction and high-accuracy tandem mass spectra, we revised the genome annotation of Leptospira interrogans serovar Lai, a free-living pathogenic spirochete responsible for leptospirosis, providing substantial peptide evidence for novel genes and new gene boundaries. Subsequently, we presented a high-coverage proteome analysis of protein expression and multiple posttranslational modifications （PTMs）. Approximately 64.3% of the predicted L. interrogans proteins were cataloged by detecting 2 540 proteins. Meanwhile, a profile of multiple PTMs was concurrently established, containing in total 32 phosphorylated, 46 acetylated and 155 methylated proteins. The PTM systems in the serovar Lai show unique features. Unique eukaryotic-like features of L. interrogans protein modifications were demonstrated in both phosphorylation and arginine methylation. This systematic analysis provides not only comprehensive information of high-coverage protein expression and multiple modifications in prokaryotes but also a view suggesting that the evolutionarily primitive L. interrogans shares significant similarities in protein modification systems with eukaryotes.展开更多
Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused ...Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes,by interfering with the acetylation status of nuclear histone proteins,hence the name histone deacetylase inhibitors was coined.Yet,this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation,survival and cell death induction.展开更多
Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis...Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis.展开更多
Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and a...Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.展开更多
Posttranslational modifications of antibody products affect their stability,charge distribution,and drug activity and are thus a critical quality attribute.The comprehensive mapping of antibody modifications and diffe...Posttranslational modifications of antibody products affect their stability,charge distribution,and drug activity and are thus a critical quality attribute.The comprehensive mapping of antibody modifications and different charge isomers(CIs)is of utmost importance,but is challenging.We intended to quantitatively characterize the posttranslational modification status of CIs of antibody drugs and explore the impact of posttranslational modifications on charge heterogeneity.The CIs of antibodies were fractionated by strong cation exchange chromatography and verified by capillary isoelectric focusing-whole column imaging detection,followed by stepwise structural characterization at three levels.First,the differences between CIs were explored at the intact protein level using a top-down mass spectrometry approach;this showed differences in glycoforms and deamidation status.Second,at the peptide level,common modifications of oxidation,deamidation,and glycosylation were identified.Peptide mapping showed nonuniform deamidation and glycoform distribution among CIs.In total,10 N-glycoforms were detected by peptide mapping.Finally,an in-depth analysis of glycan variants of CIs was performed through the detection of enriched glycopeptides.Qualitative and quantitative analyses demonstrated the dynamics of 24 N-glycoforms.The results revealed that sialic acid modification is a critical factor accounting for charge heterogeneity,which is otherwise missed in peptide mapping and intact molecular weight analyses.This study demonstrated the importance of the comprehensive analyses of antibody CIs and provides a reference method for the quality control of biopharmaceutical analysis.展开更多
Prostatic diseases such as prostate cancer and benign prostatic hyperplasia are highly prevalent among men. The number of studies focused on the abundance and roles of intrinsically disordered proteins in prostate can...Prostatic diseases such as prostate cancer and benign prostatic hyperplasia are highly prevalent among men. The number of studies focused on the abundance and roles of intrinsically disordered proteins in prostate cancer is rather limited. The goal of this study is to analyze the prevalence and degree of disorder in proteins that were previously associated with the prostate cancer pathogenesis and to compare these proteins to the entire human proteome. The analysis of these datasets provides means for drawing conclusions on the roles of disordered proteins in this common male disease. We also hope that the results of our analysis can potentially lead to future experimental studies of these proteins to find novel pathways associated with this disease.展开更多
Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a singl...Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a single open reading frame(ORF)and requires HBV supplying surface antigens(HBsAgs)to assemble a new HDV virion.During HDV replication,two isoforms of a delta antigen,a small delta antigen(SDAg)and a large delta antigen(LDAg),are produced from the same ORF of the HDV genome.The SDAg is required for HDV replication,whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA.Various clinical outcomes of HBV/HDV dual infection have been reported,but the molecular interaction between HBV and HDV is poorly understood,especially regarding howHBV and HDV compete with HBsAgs for assembling virions.In this paper,we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export.Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications(PTMs),including acetylation,phosphorylation,and isoprenylation,we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling,LDAg PTMs,and nuclear export mechanisms in this review.展开更多
TNFR1-associated death domain protein(TRADD)with arginine N-GlcNAcylation is a novel and structurally unique posttranslational modification(PTM)glycoprotein that blocks the formation of death-inducing signaling comple...TNFR1-associated death domain protein(TRADD)with arginine N-GlcNAcylation is a novel and structurally unique posttranslational modification(PTM)glycoprotein that blocks the formation of death-inducing signaling complex(DISC),orchestrating host nuclear factorκB(NF-κB)signaling in entero-pathogenic Escherichia coli(EPEC)-infected cells.This particular glycosylated modification plays an extremely vital role for the effective colonization and pathogenesis of pathogens in the gut.Herein we describe the total synthesis of TRADD death domain(residues 195-312)with arginine235 NGlcNAcylation(Arg-GIcNAc TRADD(195-312)).Two longish peptidyl fragments of the wild-type primary sequence were obtained by robust,microwave-assisted,highly efficient,solid-phase peptide synthesis(SPPS),the N-GlcNAcylated sector was built by total synthesis and attached specifically to resinbound peptide with an unprotected ornithine residue via silver-promoted on-resin guanidinylation,ArgGlcNAc TRADD(195-312)was constructed by hydrazide-based native chemical ligation(NCL).The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of other proteins with Arg-GIcNAc modification and to pave the way for the related chemically biological study.展开更多
Among various histones, histone H1 proteins have been appreciated for their multiple functions in diverse biological processes. In addition to being a structural protein in chromatin, H1 proteins also play critical ro...Among various histones, histone H1 proteins have been appreciated for their multiple functions in diverse biological processes. In addition to being a structural protein in chromatin, H1 proteins also play critical roles in cell cycle, gene expression, and development. Recent studies reveal the possible effects of H1 in some diseases, such as cancer and neurodegenerative diseases. Here, we review different variants of HI, the functions, and post translational modifications of ill variants are also discussed.展开更多
Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening pa...Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening parasites affecting people in Sub-saharan Africa or in the Americas. In these parasites the classic view of regulation of transcription initiation to modulate the products of a given gene cannot be applied. This is due to the presence of transcription start sites that give rise to long polycistronic units that need to be processed costranscriptionally by trans-splicing and polyadenylation to give mature monocistronic mRNAs. Posttranscriptional mechanisms such as mRNA degradation and translational repression are responsible for the final synthesis of the required protein products. In this context, RNA-binding proteins(RBPs) in trypanosomes have a relevant role as modulators of mRNA abundance and translational repression by associating to the 3' untranslated regions in mRNA. Many different RBPs have been proposed to modulate cohorts of mRNAs in trypanosomes. However, the current understanding of their functions lacks a dynamic view on the different steps at which these RBPs are regulated. Here, we discuss different evidences to propose regulatory events for different RBPs in these parasites. These events vary from regulated developmental expression, to biogenesis of cytoplasmic ribonucleoprotein complexes in the nucleus, and condensation of RBPs and mRNA into large cytoplasmic granules. Finally, we discuss how newly identified posttranslational modifications of RBPs and mRNA metabolism-related proteins could have an enormous impact on the modulation of m RNA abundance. To understand these modifications is especially relevant in these parasites due to the fact that the enzymes involved could be interesting targets for drug therapy.展开更多
Plants are exposed to environmental stress,in natural and agricultural conditions.Nitric oxide(NO),a small gaseous molecule which plays important roles in plants,has been involved in many physiological processes,and e...Plants are exposed to environmental stress,in natural and agricultural conditions.Nitric oxide(NO),a small gaseous molecule which plays important roles in plants,has been involved in many physiological processes,and emerged as an important endogenous signaling molecule in the adaptation of plants to biotic and abiotic stress.NO is produced from a variety of enzymatic and non enzymatic sources,which are not yet fully understood.Also,NO and reactive nitrogen species(RNS)can produce posttranslational modifications affecting protein function.Nitrate reductase,a key enzyme in the nitrogen metabolism,is a proposed source of NO in plants which could be affected by posttranslational modifications.Thus,different pathways seem to be involved and can also regulate NO synthesis in the plant cell under physiological or stress conditions.However,how the levels of NO are reached in such time and place to fulfill its functions,are still puzzles to elucidate.展开更多
基金supported by Mayo Clinic Foundation(MC-HH999 to Haojie Huang).
文摘Prostate cancer(PCa)is the most commonly diagnosed cancer among men in western countries.Androgen receptor(AR)signaling plays key roles in the development of PCa.Androgen deprivation therapy(ADT)remains the standard therapy for advanced PCa.In addition to its ligand androgen,accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa,especially in castration resistant prostate cancer(CRPC).To date,a number of posttranscriptional modifications of AR have been identified,including phosphorylation(e.g.by CDK1),acetylation(e.g.by p300 and recognized by BRD4),methylation(e.g.by EZH2),ubiquitination(e.g.by SPOP),and SUMOylation(e.g.by PIAS1).These modifications are essential for the maintenance of protein stability,nuclear localization and transcriptional activity of AR.This review summarizes posttranslational modifications that influence androgen-dependent and-independent activities of AR,PCa progression and therapy resistance.We further emphasize that in addition to androgen,posttranslational modification is another important way to regulate AR activity,suggesting that targeting AR posttranslational modifications,such as proteolysis targeting chimeras(PROTACs)of AR,represents a potential and promising alternate for effective treatment of CRPC.Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.
文摘Posttranslational modifications are a class of important cellular activities in various bio-chemical processes including signalling trans-duction, gene/metabolite networks, and disease development. It has been found that multiple posttranslational modifications with the same or different modification residues can co-exist in the same protein and this co-occurrence is critical to signalling networks in cells. Although some biological studies have spotted this phe-nomenon, little bioinformatics study has been carried out for understanding its mechanism. Four data sets were downloaded from NCBI for the study. The joint probabilities of any two neighbouring posttranslational modification sites of different modification residues were analyzed. The Bayesian probabilistic network was derived for visualizing the relationship be-tween a target modification and the contributing modifications as the predictive factors.
基金supported by Deutsche Forschungsgemeinschaft grant Ka502/19-3 to D.K.
文摘In a recent article published in Cell,He and colleagues reported that vitamin C(VitC)modifies lysine residues in proteins and peptides,thereby forming vitcyl-lysine,a process they have called vitcylation.They show that vitcylation of signal transducer and activator of transcription-1(STAT1)increases its phosphorylation and thereby promotes interferon pathway activation in cancer cells and anti-tumor immunity.
基金supported by grants from the National Natural Science Foundation of China(31970893,32270976)the Natural Science Foundation of Guangdong Province(2022A1515012541)+4 种基金the Guangdong Natural Science Fund for Distinguished Young Scholars(2016A030306004)the Fundamental Research Funds for the Central Universities(2023kypt18,2023ptpy67,19ykzd39,19ykpy43)the China Postdoctoral Science Foundation(2022M723661)the 111 Project(No.B12003,B13037)the Open Project of the Key Laboratory of Tropical Disease Control(Sun Yat-sen University),Ministry of Education(2020kfkt08).
文摘The NLRP3 inflammasome functions as an inflammatory driver,but its relationship with lipid metabolic changes in early sepsis remains unclear.Here,we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine(LPC)and was positively correlated with the severity of sepsis.GITR is a costimulatory molecule that is mainly expressed on T cells,but its function in macrophages is largely unknown.Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis.Furthermore,in vivo studies using either cecal ligation and puncture(CLP)or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality,while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1βdeficiency attenuated sepsis severity/lethality.Mechanistically,GITR specifically enhanced inflammasome activation by regulating the posttranslational modification(PTM)of NLRP3.GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation,leading to decreasing ubiquitination but increasing acetylation of NLRP3.Overall,these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury,suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases.
基金the National Natural Science Foundation of China(Grant No.32070777 to F.N.).
文摘Intermediate filaments(IFs)in human cells are the products of six distinct gene families,all sharing homology in a core rod domain.These IFs assemble into non-polar polymers,providing cytoplasmic and nuclear mechanical support.Recent research has revealed the active and dynamic properties of IFs and their binding partners.This regulation extends beyond cell mechanics to include migration,mechanotransduction,and tumor growth.Therefore,this comprehensive review aims to catalog all human IF genes and IF-associated proteins(IFAPs),detailing their names,sizes,functions,associated human diseases,relevant literature,and links to resources like UniProt and the Protein Atlas database.These links provide access to additional information such as protein structure,subcellular localization,disease-causing mutations,and pathology.Using this catalog,we will provide an overview of the current understanding of the biological functions of IFs and IFAPs.This overview is crucial for identifying gaps in their characterization and understanding IF-mediated mechanotransduction.Additionally,we will consider potential future research directions.
基金This study was supported by the National Key R&D Program of China(2018YFC1313304 and 2018YFC1313300)the National Natural Science Foundation of China(82073112,82022052 and 81871951).
文摘Altered metabolism is a hallmark of cancer,and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors.It is well recognized that long noncoding RNAs(lncRNAs)regulate energy metabolism in cancer.However,lncRNA-mediated posttranslational modifications and metabolic reprogramming are unclear at present.In this review,we summarized the current understanding of the interactions between the alterations in cancer-associated energy metabolism and the lncRNA-mediated posttranslational modifications of metabolic enzymes,transcription factors,and other proteins involved in metabolic pathways.In addition,we discuss the mechanisms through which these interactions contribute to tumor initiation and progression,and the key roles and clinical significance of functional lncRNAs.We believe that an in-depth understanding of lncRNA-mediated cancer metabolic reprogramming can help to identify cellular vulnerabilities that can be exploited for cancer diagnosis and therapy.
基金funded by the National Natural Science Foundation of China(32170185,22011530161,31801166,and 91854101)the Natural Science Foundation of Chongqing,China(cstc2021jcyj-msxmX0030 and CSTB2022NSCQ-MSX0463)+2 种基金the Venture Innovation Support Program for Chongqing Overseas Returnees(cx2022066)the Fundamental Research Funds for the Central Universities(2022CDJYGRH-002)the National Training Program of Innovation and Entrepreneurship for Undergraduates(202210611088).
文摘Legionella pneumophila is a Gram-negative bacterium ubiquitously present in freshwater environments and causes a serious type of pneumonia called Legionnaires’disease.During infections,L.pneumophila releases over 300 effector proteins into host cells through an Icm/Dot type IV secretion system to manipulate the host defense system for survival within the host.Notably,certain effector proteins mediate posttranslational modifications(PTMs),serving as useful approaches exploited by L.pneumophila to modify host proteins.Some effectors catalyze the addition of host protein PTMs,while others mediate the removal of PTMs from host proteins.In this review,we summarize L.pneumophila effector-mediated PTMs of host proteins,including phosphorylation,ubiquitination,glycosylation,AMPylation,phosphocholination,methylation,and ADP-ribosylation,as well as dephosphorylation,deubiquitination,deAMPylation,deADP-ribosylation,dephosphocholination,and delipidation.We describe their molecular mechanisms and biological functions in the regulation of bacterial growth and Legionella-containing vacuole biosynthesis and in the disruption of host immune and defense machinery.
文摘Glyceraldehyde-3-phosphate dehydrogenase （GAPDH）, initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and pnsttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 （HIF-1）, p53, nitric oxide （NO）, and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications （PTMs） occurring in GAPDH in cancer cells result in new activities unrelated to the original glycnlytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described.
文摘The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation to ensure its proper function. Defects in PTEN regulation have a profound impact on carcinogenesis. In this review, we briefly discuss recent advances concerning PTEN regulation and how such knowledge facilitates our understanding and further exploration of PTEN biology. The carboxyl-tail of PTEN, which appears to be associated with multiple types of posttranslational regulation, will be under detailed scrutiny. Further, a comparative analysis of PTEN and p53 suggests while p53 needs to be activated to suppress tumorigenesis （a dormant gatekeeper）, PTEN is probably a constitutive surveillant against cancer development, thus a default gatekeeper.
文摘Leptospirosis is a widespread zoonotic disease caused by pathogenic spirochetes of the genus Leptospira that infects humans and a wide range of animals. By combining computational prediction and high-accuracy tandem mass spectra, we revised the genome annotation of Leptospira interrogans serovar Lai, a free-living pathogenic spirochete responsible for leptospirosis, providing substantial peptide evidence for novel genes and new gene boundaries. Subsequently, we presented a high-coverage proteome analysis of protein expression and multiple posttranslational modifications （PTMs）. Approximately 64.3% of the predicted L. interrogans proteins were cataloged by detecting 2 540 proteins. Meanwhile, a profile of multiple PTMs was concurrently established, containing in total 32 phosphorylated, 46 acetylated and 155 methylated proteins. The PTM systems in the serovar Lai show unique features. Unique eukaryotic-like features of L. interrogans protein modifications were demonstrated in both phosphorylation and arginine methylation. This systematic analysis provides not only comprehensive information of high-coverage protein expression and multiple modifications in prokaryotes but also a view suggesting that the evolutionarily primitive L. interrogans shares significant similarities in protein modification systems with eukaryotes.
基金Supported by Supported by a Research Grant of the University Medical Center Giessen and Marburg
文摘Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes,by interfering with the acetylation status of nuclear histone proteins,hence the name histone deacetylase inhibitors was coined.Yet,this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation,survival and cell death induction.
文摘Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis.
基金Work at the authors’laboratories is supported by grants from"la Caixa"FoundationGrant Agreement LCF/PR/HR21/52410002+4 种基金EJP RD COFUND-EJP N°825575"Alexander"to DPS and MPAgencia Estatal de Investigacion,MICINN and ERDF Grant No.RTI2018-097624-B-I00 and PID2021-126827OB-I00 to DPSgrants from the Swedish Research Council(2017-02255)ALF Gothenburg(146051)The Swedish Society for Medical Research,Hj?rnfonden,S?derberg’s Foundations,Hagstr?mer’s Foundation Millennium,Ami?v’s Foundation,E.Jacobson’s Donation Fund,the Swedish Stroke Foundation,NanoNet COST Action(BM1002),EU FP 7 Program TargetBraln(279017)to MP。
文摘Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.
基金the financial support from the National Key Program for Basic Research of China(Grant Nos.:2018YFC0910302 and 2017YFF0205400)the National Natural Science Foundation of China(Grant No.:81530021)Innovation Foundation of Medicine(Grant Nos.:BWS14J052 and 16CXZ027)
文摘Posttranslational modifications of antibody products affect their stability,charge distribution,and drug activity and are thus a critical quality attribute.The comprehensive mapping of antibody modifications and different charge isomers(CIs)is of utmost importance,but is challenging.We intended to quantitatively characterize the posttranslational modification status of CIs of antibody drugs and explore the impact of posttranslational modifications on charge heterogeneity.The CIs of antibodies were fractionated by strong cation exchange chromatography and verified by capillary isoelectric focusing-whole column imaging detection,followed by stepwise structural characterization at three levels.First,the differences between CIs were explored at the intact protein level using a top-down mass spectrometry approach;this showed differences in glycoforms and deamidation status.Second,at the peptide level,common modifications of oxidation,deamidation,and glycosylation were identified.Peptide mapping showed nonuniform deamidation and glycoform distribution among CIs.In total,10 N-glycoforms were detected by peptide mapping.Finally,an in-depth analysis of glycan variants of CIs was performed through the detection of enriched glycopeptides.Qualitative and quantitative analyses demonstrated the dynamics of 24 N-glycoforms.The results revealed that sialic acid modification is a critical factor accounting for charge heterogeneity,which is otherwise missed in peptide mapping and intact molecular weight analyses.This study demonstrated the importance of the comprehensive analyses of antibody CIs and provides a reference method for the quality control of biopharmaceutical analysis.
文摘Prostatic diseases such as prostate cancer and benign prostatic hyperplasia are highly prevalent among men. The number of studies focused on the abundance and roles of intrinsically disordered proteins in prostate cancer is rather limited. The goal of this study is to analyze the prevalence and degree of disorder in proteins that were previously associated with the prostate cancer pathogenesis and to compare these proteins to the entire human proteome. The analysis of these datasets provides means for drawing conclusions on the roles of disordered proteins in this common male disease. We also hope that the results of our analysis can potentially lead to future experimental studies of these proteins to find novel pathways associated with this disease.
基金Supported by Grants(CMRPD-1C0811)from Chang Gung Memorial Hospital,the National Science Council and the National Health Research Institute to Lo SJ
文摘Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a single open reading frame(ORF)and requires HBV supplying surface antigens(HBsAgs)to assemble a new HDV virion.During HDV replication,two isoforms of a delta antigen,a small delta antigen(SDAg)and a large delta antigen(LDAg),are produced from the same ORF of the HDV genome.The SDAg is required for HDV replication,whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA.Various clinical outcomes of HBV/HDV dual infection have been reported,but the molecular interaction between HBV and HDV is poorly understood,especially regarding howHBV and HDV compete with HBsAgs for assembling virions.In this paper,we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export.Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications(PTMs),including acetylation,phosphorylation,and isoprenylation,we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling,LDAg PTMs,and nuclear export mechanisms in this review.
基金the National Natural Science Foundation of China (Nos.91849129,21807112)PLA Youth Medical Science and Technology Youth Development Program (No.16QNP086)Foundation of Second Military Medical University (No.2016JS11)
文摘TNFR1-associated death domain protein(TRADD)with arginine N-GlcNAcylation is a novel and structurally unique posttranslational modification(PTM)glycoprotein that blocks the formation of death-inducing signaling complex(DISC),orchestrating host nuclear factorκB(NF-κB)signaling in entero-pathogenic Escherichia coli(EPEC)-infected cells.This particular glycosylated modification plays an extremely vital role for the effective colonization and pathogenesis of pathogens in the gut.Herein we describe the total synthesis of TRADD death domain(residues 195-312)with arginine235 NGlcNAcylation(Arg-GIcNAc TRADD(195-312)).Two longish peptidyl fragments of the wild-type primary sequence were obtained by robust,microwave-assisted,highly efficient,solid-phase peptide synthesis(SPPS),the N-GlcNAcylated sector was built by total synthesis and attached specifically to resinbound peptide with an unprotected ornithine residue via silver-promoted on-resin guanidinylation,ArgGlcNAc TRADD(195-312)was constructed by hydrazide-based native chemical ligation(NCL).The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of other proteins with Arg-GIcNAc modification and to pave the way for the related chemically biological study.
基金Supported by the National Basic Research Program of China(2012CB524901)the Natural Science Foundation of China(31271370,81100687)the Program for New Century Excellent Talents in University(NECT10-0623)
文摘Among various histones, histone H1 proteins have been appreciated for their multiple functions in diverse biological processes. In addition to being a structural protein in chromatin, H1 proteins also play critical roles in cell cycle, gene expression, and development. Recent studies reveal the possible effects of H1 in some diseases, such as cancer and neurodegenerative diseases. Here, we review different variants of HI, the functions, and post translational modifications of ill variants are also discussed.
基金Supported by The Agencia Nacional de Promoción Científica y Tecnológica(ANPCyT)to Alejandro Cassola
文摘Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening parasites affecting people in Sub-saharan Africa or in the Americas. In these parasites the classic view of regulation of transcription initiation to modulate the products of a given gene cannot be applied. This is due to the presence of transcription start sites that give rise to long polycistronic units that need to be processed costranscriptionally by trans-splicing and polyadenylation to give mature monocistronic mRNAs. Posttranscriptional mechanisms such as mRNA degradation and translational repression are responsible for the final synthesis of the required protein products. In this context, RNA-binding proteins(RBPs) in trypanosomes have a relevant role as modulators of mRNA abundance and translational repression by associating to the 3' untranslated regions in mRNA. Many different RBPs have been proposed to modulate cohorts of mRNAs in trypanosomes. However, the current understanding of their functions lacks a dynamic view on the different steps at which these RBPs are regulated. Here, we discuss different evidences to propose regulatory events for different RBPs in these parasites. These events vary from regulated developmental expression, to biogenesis of cytoplasmic ribonucleoprotein complexes in the nucleus, and condensation of RBPs and mRNA into large cytoplasmic granules. Finally, we discuss how newly identified posttranslational modifications of RBPs and mRNA metabolism-related proteins could have an enormous impact on the modulation of m RNA abundance. To understand these modifications is especially relevant in these parasites due to the fact that the enzymes involved could be interesting targets for drug therapy.
文摘Plants are exposed to environmental stress,in natural and agricultural conditions.Nitric oxide(NO),a small gaseous molecule which plays important roles in plants,has been involved in many physiological processes,and emerged as an important endogenous signaling molecule in the adaptation of plants to biotic and abiotic stress.NO is produced from a variety of enzymatic and non enzymatic sources,which are not yet fully understood.Also,NO and reactive nitrogen species(RNS)can produce posttranslational modifications affecting protein function.Nitrate reductase,a key enzyme in the nitrogen metabolism,is a proposed source of NO in plants which could be affected by posttranslational modifications.Thus,different pathways seem to be involved and can also regulate NO synthesis in the plant cell under physiological or stress conditions.However,how the levels of NO are reached in such time and place to fulfill its functions,are still puzzles to elucidate.
