Peptidylarginine deiminases are a family of calcium-activated enzymes with multifaceted roles in physiological and pathological processes,including in the central nervous system.Peptidylarginine deiminases cause post-...Peptidylarginine deiminases are a family of calcium-activated enzymes with multifaceted roles in physiological and pathological processes,including in the central nervous system.Peptidylarginine deiminases cause post-translational deimination/citrullination,leading to changes in structure and function of a wide range of target proteins.Deimination can facilitate protein moonlighting,modify protein-protein interaction,cause protein dysfunction and induce inflammatory responses.Peptidylarginine deiminases also regulate the biogenesis of extracellular vesicles,which play important roles in cellular communication through transfer of extracellular vesicle-cargo,e.g.,proteins and genetic material.Both peptidylarginine deiminases and extracellular vesicles are linked to a number of pathologies,including in the central nervous system,and their modulation with pharmacological peptidylarginine deiminase inhibitors have shown great promise in several in vitro and in vivo central nervous system disease models.Furthermore,extracellular vesicles derived from mesenchymal stem cells have been assessed for their therapeutic application in central nervous system injury.As circulating extracellular vesicles can be used as non-invasive liquid biopsies,their specific cargo-signatures(including deiminated proteins and microRNAs)may allow for disease“fingerprinting”and aid early central nervous system disease diagnosis,inform disease progression and response to therapy.This mini-review discusses recent advances in the field of peptidylarginine deiminase and extracellular vesicle research in the central nervous system,focusing on several central nervous system acute injury,degeneration and cancer models.展开更多
Objective To study the expression level of peptidylarginine deiminase 4(PADI4) and protein tyrosine phosphatase nonreceptor type 22(PTPN22) in the synovium of rat model of collagen-induced arthritis, and to explore th...Objective To study the expression level of peptidylarginine deiminase 4(PADI4) and protein tyrosine phosphatase nonreceptor type 22(PTPN22) in the synovium of rat model of collagen-induced arthritis, and to explore their possible therapeutic role in rheumatoid arthritis. Methods Thirty-two female Wistar rats weighing 100±20 g were randomly assigned into 3-week collagen-induced arthritis(CIA) model group(n=8), 4-week CIA model group(n=8), 6-week CIA model group(n=8), and the control group(n=8). The body weight changes of each group were recorded. The expression levels of PADI4 and PTPN22 were detected and compared by the methods of immunohistochemical staining and Western blot. Results Arthritis of rat began to form 14 days after sensitization and the joint swelling reached peak at 28 days. The weights of the rats slowly grew both in CIA model groups and the control group. Immunohistochemical staining results showed that the positive expression of PADI4 and PTPN22 was mainly located in cartilage peripheral mononuclear cells, the cytoplasm of infiltrated cells, and bone marrow cavity. There were significant differences in the optical density of PADI4 and PTPN22 among CIA model groups and the control group(PADI4, 0.2898±0.012, 0.2982±0.022, 0.2974±0.031, 0.2530±0.013 in 3-week CIA model, 4-week CIA model, 6-week CIA model and control groups; PTPN22, 0.2723±0.004, 0.2781±0.010, 0.2767±0.008, 0.2422±0.019; all P <0.05). The expression bands of PADI4 were observed in Western blot 3 weeks after initial immunization, the thickest in the 4th week, and decreased in the 6th week. The expression bands of PTPN2 were observed at all the time points, with no obvious time-dependent trend. Conclusions PADI4 and PTPN22 are obviously correlated with CIA in rat model. PADI4 is expressed at early stage of the disease, while the expression of PTPN22 sustains throughout the course.展开更多
Objective： The aim of the research was to study peptidylarginine deiminase type 4 （PAD4/PADI4） expression and its tumodgenic mechanism in hepatocellular carcinomas. Methods： Expressions of PADI4 and p53 were inves...Objective： The aim of the research was to study peptidylarginine deiminase type 4 （PAD4/PADI4） expression and its tumodgenic mechanism in hepatocellular carcinomas. Methods： Expressions of PADI4 and p53 were investigated in tumors and non-tumor tissues by Western blot in patients with hepatocellular carcinomas. We constructed plasmid of PADI4-Flag and transfected it in Hela cells to investigate the mechanism. Results： Western blot analysis showed higher PADI4 expression in hepatocellular carcinomas than in the surrounding healthy tissues. Furthermore, by Western blot, we detected decreased p53 levels in the tumor tissues of patients with hepatocellular carcinomas compared to surrounding healthy tissues. In Hela cells transfected with PcDNA3.0-Flag-PADI4 plasmid, the expression of p53 decreased obviously. Conclusion： Our results suggest that PADI4 elevated in the tissues of hepatocellular carcinomas and induced tumorigenic by down-regulating p53 expression.展开更多
A novel Enterococcus faecalis strain designated N J402 was found with high activity of arginine deiminase （ADI）. The optimum condition for catalytic activity was determined in terms of temperature （about 40℃）, th...A novel Enterococcus faecalis strain designated N J402 was found with high activity of arginine deiminase （ADI）. The optimum condition for catalytic activity was determined in terms of temperature （about 40℃）, thermostability （available 37℃） and pH （6-7）. The effects of substrate and product concentration were studied. The effects of various metal ions added in reaction mixtures on the biocatalyst were investigated and ADI of N J402 was found to exhibit Co^2＋ dependence, different from previous reports. Surfactant, cetyl trimethyl ammonium bromide, was one of the most important keys for producing L-citrulline. The enzyme in resting cells possessed the quality of high stability for reuse.展开更多
Histone citrullination,an important post-translational modification mediated by peptidyl arginine deiminases,is essential for many physiological processes and epigenetic regulation.However,the causal relationship betw...Histone citrullination,an important post-translational modification mediated by peptidyl arginine deiminases,is essential for many physiological processes and epigenetic regulation.However,the causal relationship between histone citrullination and specific gene regulation remains unresolved.In this study,we develop a programmable epigenetic editor by fusing the peptidyl arginine deiminase(PAD)PPAD from Porphyromonas gingivalis with d Cas9.With the assistance of g RNA,PPAD-d Cas9 can recruit PPADs to specific genomic loci,enabling direct manipulation of the epigenetic landscape and regulation of gene expression.Our citrullination editor allows for the site-specific manipulation of histone H3R2,8,17 and H3R26 at target human gene loci,resulting in the activation or suppression of different genes in a locus-specific manner.Moreover,the epigenetic effects of the citrullination editor are specific and sustained.This epigenetic editor offers an accurate and efficient tool for exploring gene regulation of histone citrullination.展开更多
The murine peptidylarginine deiminase (PAD) has five isoforms encoded by different genes and participates in a variety of cellular functions through the citrullination of target proteins. The crystal structure of huma...The murine peptidylarginine deiminase (PAD) has five isoforms encoded by different genes and participates in a variety of cellular functions through the citrullination of target proteins. The crystal structure of human PAD4 with a dimeric form was previously solved because of the enzyme’s relevance to rheumatoid arthritis. PAD6, abundant in mouse oocytes and eggs, is believed to take part in early events of embryogenesis, but its biochemical properties are little understood. Here we have purified and characterized a recombinant PAD6. A PAD6 cDNA was cloned from mouse ovary RNA and expressed in Escherichia coli through pET29 and pGEX vectors. When benzoyl-L-arginine ethyl ester was used as a substrate, no appreciable activity was detected with a cell homogenate under conditions where a human PAD4 cDNA caused significant activity. Both proteins were affinity-purified to near homogeneity. The circular dichroism spectra of PAD6 and human PAD4 were similar in the far ultraviolet region. On molecular sieving, PAD6 was eluted faster than human PAD4. The cross-linking of PAD6 with dimethyl suberimidate clearly showed six bands on an sodium dodecyl sulfate-polyacrylamide gel. These results indicate that PAD6 can constitute a hexameric structure. The purified PAD6 still showed no enzymatic activity. This unique structure and loss in enzymatic activity is strongly suggested to favor the formation of egg cytoplasmic sheets as the architectural protein.展开更多
Neutrophil extracellular traps(NETs)have emerged as key mediators of cardiovascular diseases(CVDs),linking innate immune activation to vascular injury,thrombosis,and maladaptive remodeling.This review synthesizes rece...Neutrophil extracellular traps(NETs)have emerged as key mediators of cardiovascular diseases(CVDs),linking innate immune activation to vascular injury,thrombosis,and maladaptive remodeling.This review synthesizes recent insights into the molecular and cellular pathways driving NET formation,including post-translational modifications,metabolic reprogramming,inflammasome signaling,and autophagy.It highlights the role of NETs in atherosclerosis,thrombosis,myocardial ischemia-reperfusion injury,and hypertension,emphasizing common control points such as peptidylarginine deiminase 4(PAD4)-dependent histone citrullination and nicotinamide adenine dinucleotide phosphate oxidases 2(NOX2)-mediated oxidative stress.Mechanistic interpretation of circulating biomarkers,includingmyeloperoxidase(MPO)-DNA complexes,citrullinated histoneH3,and cell-free DNA,provides a translational bridge between NET biology and patient stratification.Therapeutic strategies targeting NETs are examined through three main approaches:inhibition of NET initiation,enhancement of chromatin clearance,and neutralization of toxic extracellular components,with attention to both established and emerging interventions.In contrast to previous reviews,this study highlights the novelty of a mechano-therapeutic framework by providing a mechanistic roadmap linking NET formation pathways to therapeutic targeting in cardiovascular disease.Moving forward,integrating mechanistic information with biomarker discovery,precision profiling,and targeted therapies offers innovative strategies to reduce vascular inflammation and improve outcomes in cardiovascular disease.展开更多
Protein citrullination involves the deimination of arginine or methylarginine resi-dues in peptide chains to form citrulline by peptidyl arginine deiminases.This process is an important protein post-translational modi...Protein citrullination involves the deimination of arginine or methylarginine resi-dues in peptide chains to form citrulline by peptidyl arginine deiminases.This process is an important protein post-translational modification that affects molecular structure and func-tion of various proteins,including histones.In recent years,protein citrullination has attracted widespread attention for its influence on gene transcription.Studies on the impact of protein citrullination modification on chromatin structure remodeling and the establishment of gene regulatory networks have made rapid progress.In this review,we briefly summarize the phys-iological functions of protein citrullination modification.Specifically,we comprehensively outline the latest progress in the study of the role of protein citrullination modification in gene transcription regulation,focusing on the interaction of protein citrullination with other post-translational modifications.展开更多
Introduction:Scarring and non-scarring alopecias have rarely been described to occur together in the same patient.Distinguishing these two different types of alopecia is important as treatment and prognosis can be dif...Introduction:Scarring and non-scarring alopecias have rarely been described to occur together in the same patient.Distinguishing these two different types of alopecia is important as treatment and prognosis can be different.Case presentation:Here,we report the first case of simultaneous alopecia areata(AA)and central centrifugal cicatricial alopecia(CCCA)in a 35-year-old woman.New alopecic patches were noted on her frontal and vertex scalp.Biopsy of the frontal scalp revealed miniaturized hair follicles and dense lymphocytic infiltrate surrounding the hair bulbs,consistent with AA;while biopsy of the vertex scalp revealed decreased hair follicles,perifollicular fibroplasia with eccentric atrophy of the follicular epithelium,and premature desquamation of the inner root sheath at the level of the lower isthmus,consistent with CCCA.Discussion:Proposed mechanisms of these two alopecia types occurring together include loss of immune privilege,genetic predisposition,as well as unknown external factors that trigger an autoimmune lymphocytic response.Most recently,the peptidylarginine deiminase type III gene has been implicated in both diseases.Although treatment options can overlap between thetwo diseases,treatment response can differ and CCCA tendsto have a worse prognosis.Conclusion:Awareness of this concomitant presentation of two alopecic types is important for appropriate treatment and prognostication.展开更多
Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis(RA),but the relationship between the two phenomena remains unclear.We explored whether and how cholinergic dysfunction ...Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis(RA),but the relationship between the two phenomena remains unclear.We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA.Cholinergic function and protein citrullination levels in patients with RA and collageninduced arthritis(CIA)mice were collected.In both neuron-macrophage coculture system and CIA mice,the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases(PADs)was assessed by immunofluorescence.The key transcription factors for PAD4 expression were predicted and validated.Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues.The cholinergic or alpha7 nicotinic acetylcholine receptor(a7nAChR)deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo,respectively.Especially,the activation deficiency of a7nAChR induced the earlier onset and aggravation of CIA.Furthermore,deactivation of a7nAChR increased the expression of PAD4 and specificity protein-3(SP3)in vitro and in vivo.Our results suggest that cholinergic dysfunction-induced deficient a7nAChR activation,which induces the expression of SP3 and its downstream molecule PAD4,accelerating protein citrullination and the development of RA.展开更多
Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1(ASS1)that is necessary for synthesis of L-arginine.These cancers must import arginine for survival and growth,and this reliance can ...Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1(ASS1)that is necessary for synthesis of L-arginine.These cancers must import arginine for survival and growth,and this reliance can be targeted by arginine-degrading extracellular enzymatic drugs,most commonly PEGylated arginine deiminase.These enzymes can become targets of the immune system,reducing their effectiveness,but PEGylation improves the in vivo stability.Arginine deprivation causes cell death in some cancers,but others gain resistance by expressing ASS1 after a starvation response is induced.Other resistance mechanisms are possible and explored,but these have not been observed specifically in response to arginine deprivation.Future studies,especially focusing on the mechanisms of ASS1 upregulation and metabolic adaptations,may yield insights into preventing or taking advantage of resistance adaptations to make arginine deprivation therapy more effective.展开更多
Background Cathelicidin(CAMP),plays important roles in pathogen defense,immune regulation,and epithelial barrier maintenance.While previous studies have highlighted its protective function,the post-translational modif...Background Cathelicidin(CAMP),plays important roles in pathogen defense,immune regulation,and epithelial barrier maintenance.While previous studies have highlighted its protective function,the post-translational modifications and downstream immune-metabolic effects of CAMP in the pathogenesis of inflammatory bowel disease remain unclear.Methods A dextran sodium sulfate(DSS)-induced colitis mouse model was employed to assess the role of CAMP and its citrullination mediated by peptidyl arginine deiminase 4(PAD4).Proteomic and metaproteomic analyses were performed to investigate microbiota composition and functional shifts.We generated gene-deficient mouse models,CAMP knockout(KO)and PAD4-KO mice,to dissect molecular mechanisms.Epithelial integrity,inflammatory markers,and immune responses have been evaluated at both the protein and mRNA levels.Bone marrow-derived dendritic cells and primary CD4⁺T cells were co-cultured to examine the effects of CAMP-related metabolites on antigen presentation and Th17 differentiation.Furthermore,we evaluated the impact of CAMP peptide supplementation and the effects of CAMP-KO mice on DSS-induced colitis.Results CAMP citrullination was significantly elevated in DSS-induced colitis mice but restored by PAD4 deletion.Citrullination was found to reduce CAMP protein levels without affecting its transcriptional expression.The absence of CAMP exacerbated intestinal inflammation in DSS-treated mice.Metaproteomic analysis identified 70 differentially expressed proteins and 15 altered microbiota families associated with CAMP deficiency.Elevated levels of arginase-1 and its metabolites,particularly polyamines,enhanced dendritic cell maturation and increased Th17 polarization in CAMP-KO mice.Conclusions Our findings highlight that the protein level of CAMP decreased after PAD4-mediated citrullination,thus playing a vital role in regulating taxonomic community structure,restricting arginine metabolism,and regulating dendritic cell–Th17 immune responses in IBD.展开更多
基金The work was supported in parts by a University of Westminster start-up grant to SL.
文摘Peptidylarginine deiminases are a family of calcium-activated enzymes with multifaceted roles in physiological and pathological processes,including in the central nervous system.Peptidylarginine deiminases cause post-translational deimination/citrullination,leading to changes in structure and function of a wide range of target proteins.Deimination can facilitate protein moonlighting,modify protein-protein interaction,cause protein dysfunction and induce inflammatory responses.Peptidylarginine deiminases also regulate the biogenesis of extracellular vesicles,which play important roles in cellular communication through transfer of extracellular vesicle-cargo,e.g.,proteins and genetic material.Both peptidylarginine deiminases and extracellular vesicles are linked to a number of pathologies,including in the central nervous system,and their modulation with pharmacological peptidylarginine deiminase inhibitors have shown great promise in several in vitro and in vivo central nervous system disease models.Furthermore,extracellular vesicles derived from mesenchymal stem cells have been assessed for their therapeutic application in central nervous system injury.As circulating extracellular vesicles can be used as non-invasive liquid biopsies,their specific cargo-signatures(including deiminated proteins and microRNAs)may allow for disease“fingerprinting”and aid early central nervous system disease diagnosis,inform disease progression and response to therapy.This mini-review discusses recent advances in the field of peptidylarginine deiminase and extracellular vesicle research in the central nervous system,focusing on several central nervous system acute injury,degeneration and cancer models.
基金Supported by the National Natural Science Foundation of China(81072450)
文摘Objective To study the expression level of peptidylarginine deiminase 4(PADI4) and protein tyrosine phosphatase nonreceptor type 22(PTPN22) in the synovium of rat model of collagen-induced arthritis, and to explore their possible therapeutic role in rheumatoid arthritis. Methods Thirty-two female Wistar rats weighing 100±20 g were randomly assigned into 3-week collagen-induced arthritis(CIA) model group(n=8), 4-week CIA model group(n=8), 6-week CIA model group(n=8), and the control group(n=8). The body weight changes of each group were recorded. The expression levels of PADI4 and PTPN22 were detected and compared by the methods of immunohistochemical staining and Western blot. Results Arthritis of rat began to form 14 days after sensitization and the joint swelling reached peak at 28 days. The weights of the rats slowly grew both in CIA model groups and the control group. Immunohistochemical staining results showed that the positive expression of PADI4 and PTPN22 was mainly located in cartilage peripheral mononuclear cells, the cytoplasm of infiltrated cells, and bone marrow cavity. There were significant differences in the optical density of PADI4 and PTPN22 among CIA model groups and the control group(PADI4, 0.2898±0.012, 0.2982±0.022, 0.2974±0.031, 0.2530±0.013 in 3-week CIA model, 4-week CIA model, 6-week CIA model and control groups; PTPN22, 0.2723±0.004, 0.2781±0.010, 0.2767±0.008, 0.2422±0.019; all P <0.05). The expression bands of PADI4 were observed in Western blot 3 weeks after initial immunization, the thickest in the 4th week, and decreased in the 6th week. The expression bands of PTPN2 were observed at all the time points, with no obvious time-dependent trend. Conclusions PADI4 and PTPN22 are obviously correlated with CIA in rat model. PADI4 is expressed at early stage of the disease, while the expression of PTPN22 sustains throughout the course.
文摘Objective： The aim of the research was to study peptidylarginine deiminase type 4 （PAD4/PADI4） expression and its tumodgenic mechanism in hepatocellular carcinomas. Methods： Expressions of PADI4 and p53 were investigated in tumors and non-tumor tissues by Western blot in patients with hepatocellular carcinomas. We constructed plasmid of PADI4-Flag and transfected it in Hela cells to investigate the mechanism. Results： Western blot analysis showed higher PADI4 expression in hepatocellular carcinomas than in the surrounding healthy tissues. Furthermore, by Western blot, we detected decreased p53 levels in the tumor tissues of patients with hepatocellular carcinomas compared to surrounding healthy tissues. In Hela cells transfected with PcDNA3.0-Flag-PADI4 plasmid, the expression of p53 decreased obviously. Conclusion： Our results suggest that PADI4 elevated in the tissues of hepatocellular carcinomas and induced tumorigenic by down-regulating p53 expression.
基金Supported by the Innovation Foundation of China (No. 02CJ-13-01-16).
文摘A novel Enterococcus faecalis strain designated N J402 was found with high activity of arginine deiminase （ADI）. The optimum condition for catalytic activity was determined in terms of temperature （about 40℃）, thermostability （available 37℃） and pH （6-7）. The effects of substrate and product concentration were studied. The effects of various metal ions added in reaction mixtures on the biocatalyst were investigated and ADI of N J402 was found to exhibit Co^2＋ dependence, different from previous reports. Surfactant, cetyl trimethyl ammonium bromide, was one of the most important keys for producing L-citrulline. The enzyme in resting cells possessed the quality of high stability for reuse.
基金funded by the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(TSBICIP-CXRC-048)。
文摘Histone citrullination,an important post-translational modification mediated by peptidyl arginine deiminases,is essential for many physiological processes and epigenetic regulation.However,the causal relationship between histone citrullination and specific gene regulation remains unresolved.In this study,we develop a programmable epigenetic editor by fusing the peptidyl arginine deiminase(PAD)PPAD from Porphyromonas gingivalis with d Cas9.With the assistance of g RNA,PPAD-d Cas9 can recruit PPADs to specific genomic loci,enabling direct manipulation of the epigenetic landscape and regulation of gene expression.Our citrullination editor allows for the site-specific manipulation of histone H3R2,8,17 and H3R26 at target human gene loci,resulting in the activation or suppression of different genes in a locus-specific manner.Moreover,the epigenetic effects of the citrullination editor are specific and sustained.This epigenetic editor offers an accurate and efficient tool for exploring gene regulation of histone citrullination.
文摘The murine peptidylarginine deiminase (PAD) has five isoforms encoded by different genes and participates in a variety of cellular functions through the citrullination of target proteins. The crystal structure of human PAD4 with a dimeric form was previously solved because of the enzyme’s relevance to rheumatoid arthritis. PAD6, abundant in mouse oocytes and eggs, is believed to take part in early events of embryogenesis, but its biochemical properties are little understood. Here we have purified and characterized a recombinant PAD6. A PAD6 cDNA was cloned from mouse ovary RNA and expressed in Escherichia coli through pET29 and pGEX vectors. When benzoyl-L-arginine ethyl ester was used as a substrate, no appreciable activity was detected with a cell homogenate under conditions where a human PAD4 cDNA caused significant activity. Both proteins were affinity-purified to near homogeneity. The circular dichroism spectra of PAD6 and human PAD4 were similar in the far ultraviolet region. On molecular sieving, PAD6 was eluted faster than human PAD4. The cross-linking of PAD6 with dimethyl suberimidate clearly showed six bands on an sodium dodecyl sulfate-polyacrylamide gel. These results indicate that PAD6 can constitute a hexameric structure. The purified PAD6 still showed no enzymatic activity. This unique structure and loss in enzymatic activity is strongly suggested to favor the formation of egg cytoplasmic sheets as the architectural protein.
文摘Neutrophil extracellular traps(NETs)have emerged as key mediators of cardiovascular diseases(CVDs),linking innate immune activation to vascular injury,thrombosis,and maladaptive remodeling.This review synthesizes recent insights into the molecular and cellular pathways driving NET formation,including post-translational modifications,metabolic reprogramming,inflammasome signaling,and autophagy.It highlights the role of NETs in atherosclerosis,thrombosis,myocardial ischemia-reperfusion injury,and hypertension,emphasizing common control points such as peptidylarginine deiminase 4(PAD4)-dependent histone citrullination and nicotinamide adenine dinucleotide phosphate oxidases 2(NOX2)-mediated oxidative stress.Mechanistic interpretation of circulating biomarkers,includingmyeloperoxidase(MPO)-DNA complexes,citrullinated histoneH3,and cell-free DNA,provides a translational bridge between NET biology and patient stratification.Therapeutic strategies targeting NETs are examined through three main approaches:inhibition of NET initiation,enhancement of chromatin clearance,and neutralization of toxic extracellular components,with attention to both established and emerging interventions.In contrast to previous reviews,this study highlights the novelty of a mechano-therapeutic framework by providing a mechanistic roadmap linking NET formation pathways to therapeutic targeting in cardiovascular disease.Moving forward,integrating mechanistic information with biomarker discovery,precision profiling,and targeted therapies offers innovative strategies to reduce vascular inflammation and improve outcomes in cardiovascular disease.
基金supported by the Tianjin Synthetic Biotech-nology Innovation Capacity Improvement Project(Grant No.TSBICIP-CXRC-048).
文摘Protein citrullination involves the deimination of arginine or methylarginine resi-dues in peptide chains to form citrulline by peptidyl arginine deiminases.This process is an important protein post-translational modification that affects molecular structure and func-tion of various proteins,including histones.In recent years,protein citrullination has attracted widespread attention for its influence on gene transcription.Studies on the impact of protein citrullination modification on chromatin structure remodeling and the establishment of gene regulatory networks have made rapid progress.In this review,we briefly summarize the phys-iological functions of protein citrullination modification.Specifically,we comprehensively outline the latest progress in the study of the role of protein citrullination modification in gene transcription regulation,focusing on the interaction of protein citrullination with other post-translational modifications.
文摘Introduction:Scarring and non-scarring alopecias have rarely been described to occur together in the same patient.Distinguishing these two different types of alopecia is important as treatment and prognosis can be different.Case presentation:Here,we report the first case of simultaneous alopecia areata(AA)and central centrifugal cicatricial alopecia(CCCA)in a 35-year-old woman.New alopecic patches were noted on her frontal and vertex scalp.Biopsy of the frontal scalp revealed miniaturized hair follicles and dense lymphocytic infiltrate surrounding the hair bulbs,consistent with AA;while biopsy of the vertex scalp revealed decreased hair follicles,perifollicular fibroplasia with eccentric atrophy of the follicular epithelium,and premature desquamation of the inner root sheath at the level of the lower isthmus,consistent with CCCA.Discussion:Proposed mechanisms of these two alopecia types occurring together include loss of immune privilege,genetic predisposition,as well as unknown external factors that trigger an autoimmune lymphocytic response.Most recently,the peptidylarginine deiminase type III gene has been implicated in both diseases.Although treatment options can overlap between thetwo diseases,treatment response can differ and CCCA tendsto have a worse prognosis.Conclusion:Awareness of this concomitant presentation of two alopecic types is important for appropriate treatment and prognostication.
基金supported by the“Double First-Class”University Project(CPU2022QZ31,China)。
文摘Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis(RA),but the relationship between the two phenomena remains unclear.We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA.Cholinergic function and protein citrullination levels in patients with RA and collageninduced arthritis(CIA)mice were collected.In both neuron-macrophage coculture system and CIA mice,the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases(PADs)was assessed by immunofluorescence.The key transcription factors for PAD4 expression were predicted and validated.Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues.The cholinergic or alpha7 nicotinic acetylcholine receptor(a7nAChR)deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo,respectively.Especially,the activation deficiency of a7nAChR induced the earlier onset and aggravation of CIA.Furthermore,deactivation of a7nAChR increased the expression of PAD4 and specificity protein-3(SP3)in vitro and in vivo.Our results suggest that cholinergic dysfunction-induced deficient a7nAChR activation,which induces the expression of SP3 and its downstream molecule PAD4,accelerating protein citrullination and the development of RA.
基金BAVT-reports a one year grant from Polaris,Inc.in 2014,unrelatedBasic Science Grant Funding from Pfizer,Tracon,and Merck+3 种基金consulting fees from Epizyme,Lilly,CytRX,Janssen,Immune Design,Daiichi Sankyo,Bayer,Plexxicon and Adaptimmunespeaking fees from Caris,Janseen and LillyTravel support from Lillyand is the overall principle investigator on(NCT03449901).
文摘Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1(ASS1)that is necessary for synthesis of L-arginine.These cancers must import arginine for survival and growth,and this reliance can be targeted by arginine-degrading extracellular enzymatic drugs,most commonly PEGylated arginine deiminase.These enzymes can become targets of the immune system,reducing their effectiveness,but PEGylation improves the in vivo stability.Arginine deprivation causes cell death in some cancers,but others gain resistance by expressing ASS1 after a starvation response is induced.Other resistance mechanisms are possible and explored,but these have not been observed specifically in response to arginine deprivation.Future studies,especially focusing on the mechanisms of ASS1 upregulation and metabolic adaptations,may yield insights into preventing or taking advantage of resistance adaptations to make arginine deprivation therapy more effective.
基金supported by the National Natural Science Foundation of China(grant Nos.82100587 and 82400605)the China National Postdoctoral Program for Innovative Talents(grant No.BX20220288)+5 种基金the China Postdoctoral Science Foundation(grant No.2022M720138)the Clinical Research Special Project of Shanghai Municipal Health Commission(grant No.20244Y0209)Capability Enhancement Project for Clinical Research Physician of the First Affiliated Hospital of Naval Medical University(grant No.2024LYC01)the Basic Medical Research Project of the First Affiliated Hospital of Naval Medical University(grant No.2023PY06)the Basic Medical Research Projects of Naval Medical University(grant Nos.2024MS08 and 2024QN026)the“Yuanhang”Talent Program of Naval Medical University,the“Changjian”Talent Program of Changhai Hospital of Naval Medical University,the“Changying”Talent Program of Changhai Hospital of Naval Medical University and Youth Project of Shanghai Key Laboratory(grant Nos.2025QN01 and 2025QN09).
文摘Background Cathelicidin(CAMP),plays important roles in pathogen defense,immune regulation,and epithelial barrier maintenance.While previous studies have highlighted its protective function,the post-translational modifications and downstream immune-metabolic effects of CAMP in the pathogenesis of inflammatory bowel disease remain unclear.Methods A dextran sodium sulfate(DSS)-induced colitis mouse model was employed to assess the role of CAMP and its citrullination mediated by peptidyl arginine deiminase 4(PAD4).Proteomic and metaproteomic analyses were performed to investigate microbiota composition and functional shifts.We generated gene-deficient mouse models,CAMP knockout(KO)and PAD4-KO mice,to dissect molecular mechanisms.Epithelial integrity,inflammatory markers,and immune responses have been evaluated at both the protein and mRNA levels.Bone marrow-derived dendritic cells and primary CD4⁺T cells were co-cultured to examine the effects of CAMP-related metabolites on antigen presentation and Th17 differentiation.Furthermore,we evaluated the impact of CAMP peptide supplementation and the effects of CAMP-KO mice on DSS-induced colitis.Results CAMP citrullination was significantly elevated in DSS-induced colitis mice but restored by PAD4 deletion.Citrullination was found to reduce CAMP protein levels without affecting its transcriptional expression.The absence of CAMP exacerbated intestinal inflammation in DSS-treated mice.Metaproteomic analysis identified 70 differentially expressed proteins and 15 altered microbiota families associated with CAMP deficiency.Elevated levels of arginase-1 and its metabolites,particularly polyamines,enhanced dendritic cell maturation and increased Th17 polarization in CAMP-KO mice.Conclusions Our findings highlight that the protein level of CAMP decreased after PAD4-mediated citrullination,thus playing a vital role in regulating taxonomic community structure,restricting arginine metabolism,and regulating dendritic cell–Th17 immune responses in IBD.
