Background The genes encoding adiponectin receptor 1 （ADIPOR1） and small ubiquitin-like modifier 4 （SUM04） have been linked to anti-atherogenic effects, but little is known about whether polymorphisms in the two g...Background The genes encoding adiponectin receptor 1 （ADIPOR1） and small ubiquitin-like modifier 4 （SUM04） have been linked to anti-atherogenic effects, but little is known about whether polymorphisms in the two genes, acting separately or interacting, affect risk of coronary artery disease （CAD） without diabetes. Methods We genotyped 200 CAD patients without diabetes and 200 controls without CAD or diabetes at three single-nucleotide polymorphisms （SNPs） in ADIPOR1 and one SNP in SUM04, which were chosen based on previous studies. Potential associations were also explored between these SNPs and clinical characteristics of CAD without diabetes. Results Risk alleles at three SNPs inADIPOR1 （rs7539542-G, rs7514221-C and rs3737884-G） and the G allele at SNP rs237025 in SUM04 significantly increased risk of CAD without diabetes, with ORs ranging from 1.79 to 4.44. Carriers of any of these four risk alleles showed similar adverse clinical characteristics. Compared with individuals with a CC or GC genotype, those with a GG genotype at rs3737884 were at significantly higher risk of CAD that affected the left anterior descending coronary artery （OR： 6.77, P = 0.009）, the right coronary artery （OR： 4.81, P = 0.028） or a relatively large number of vessels （P = 0.04）. Individuals carrying a risk allele at one or more of the three SNPs in ADIPOR1 as well as a risk allele at the SNP in SUM04 were at significantly higher risk of CAD without diabetes than individuals not carrying any risk alleles （OR： 5.82, 95% CI： 1.23-27.7, P= 0.013）. Conelusions SNPs in ADIPORl and SUMO4 are associated with elevated risk of CAD without diabetes, and SNPs in the two genes may interact to jointly affect disease risk.展开更多
Small ubiquitin-like modifier （SUMO） conjugation affects a broad range of processes in plants, including growth, flower initiation, pathogen defense, and responses to abiotic stress. Here, we investigate in vivo and...Small ubiquitin-like modifier （SUMO） conjugation affects a broad range of processes in plants, including growth, flower initiation, pathogen defense, and responses to abiotic stress. Here, we investigate in vivo and in vitro a SUMO conjugating enzyme with a Cys to Ser change in the active site, and show that it has a dominant negative effect. In planta expression significantly perturbs normal development, leading to growth retardation, early flowering and gene expression changes. We suggest that the mutant protein can serve as a probe to investigate sumoylation, also in plants for which poor genetic infrastructure precludes analysis via loss-of-function mutants.展开更多
Small ubiquitin-like modifier(SUMO)ylation is a key posttranslational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not ...Small ubiquitin-like modifier(SUMO)ylation is a key posttranslational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle.展开更多
Background Non-small cell lung cancer （NSCLC） is one of the most common malignant tumors.Despite the advances in therapy over the years,its mortality remains high.The aim of this study was to evaluate the expression...Background Non-small cell lung cancer （NSCLC） is one of the most common malignant tumors.Despite the advances in therapy over the years,its mortality remains high.The aim of this study was to evaluate the expression of small ubiquitin-like modifier （SUMO） proteases 1 （SENP1） in NSCLC tissues and its role in the regulation of vascular endothelial growth factor （VEGF） expression.We also investigated the association between the expression level of SENP1 and the clinicopathological features and survival of the patients.Methods A SENP1 small interfering RNA （siRNA） was constructed and transfected into the NSCLC cells.VEGF gene expression was analyzed by real-time polymerase chain reaction （RT-PCR）.Immunohistochemistry staining was used to assess the expression of SENP1 in 100 NSCLC patients and its association with the clinicopathological features and survival was analyzed.Results VEGF expression was significantly higher in NSCLC tissues than in normal lung tissues.Inhibition of SENP1 by siRNA was associated with decreased VEGF expression.SENP1 was over-expressed in 55 of the 100 NSCLC samples （55％） and was associated with a moderate and low histological tumor grade （3.6％,38.2％,and 58.2％ in high,moderate and low differentiated tumors,respectively,P=0.046）,higher T stage （10.9％ in T1,and 89.1％ in T2 and T3 tumor samples,P ＜0.001）and TNM stage （10.9％ in stage Ⅰ,and 89.1％ in stages Ⅱ and Ⅲ tumor samples,P ＜0.001）.The rate of lymph node metastasis was significantly higher in the SENP1 over-expression group （76.4％） than that in the SENP1 low expression group （33.3％,P ＜0.001）.Sixty three patients received postoperative chemotherapy,including 34 with SENP1 over-expression and 29 with SENP1 low expression.Among the 34 patients with SENP1 over-expression,22 （64.7％） patients developed recurrence or metastasis,significantly higher than those in the low expression group 27.6％ （8/29） （P=0.005）.Multivariate Cox regression analysis showed that lymph node metastasis （P=0.015）,TNM stage （P=-0.001）,and SENP1 expression level （P=0.002） were independent prognostic factors for the survival of NSCLC patients.Conclusions SENP1 may be a promising predictor of survival,a predictive factor of chemo-sensitivity for NSCLC patients,and potentially a desirable drug target for lung carcinoma target therapy.展开更多
Small ubiquitin-like modifier(SUMO)-conjugating enzymes are involved in post-translational regulatory processes in eukaryotes, including the conjugation of SUMO peptides to protein substrate(SUMOylation). SUMOylation ...Small ubiquitin-like modifier(SUMO)-conjugating enzymes are involved in post-translational regulatory processes in eukaryotes, including the conjugation of SUMO peptides to protein substrate(SUMOylation). SUMOylation plays an important role in improving plant tolerance to abiotic stress such as salt, drought, heat and cold. Herein, we reported the isolation of OsSCE1(LOC_Os10 g39120) gene encoding a SUMO-conjugating enzyme from rice(Oryza sativa cv. Nipponbare) and its functional validation in response to drought stress. The E2 enzyme, Os SCE1, is one of three key enzymes involved in the conjugation of SUMO to its target proteins. Activated SUMO is transferred to the cysteine of an E2 enzyme and then to the target lysine residue of the substrate, with or without the help of an E3 SUMO ligase. Expression of OsSCE1 was strongly induced by polyethylene glycol 6000(PEG6000) treatment, which suggested OsSCE1 may be involved in the drought stress response. Overexpression of OsSCE1(OsSCE1-OX) in Nipponbare reduced the tolerance to drought stress. Conversely, the drought tolerance was slightly improved by the knockdown of OsSCE1(OsSCE1-KD). These results were further supported by measurement of proline content in OsSCE1-OX and OsSCE1-KD transgenic lines under induced drought stress, which showed OsSCE1-KD transgenic lines accumulated higher proline content than the wild type, whereas OsSCE1-OX line had lower proline content than the wild type. These findings suggested OsSCE1 may play a role as a negative regulator in response to drought stress in rice.展开更多
SRY-related HMG-box(Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases.Post-translational modification of Sox proteins is known to alt...SRY-related HMG-box(Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases.Post-translational modification of Sox proteins is known to alter their functions in the central nervous system.Among the different types of post-translational modification,small ubiquitin-like modifier(SUMO) modification of Sox proteins has been shown to modify their transcriptional activity.Here,we review the mechanisms of three Sox proteins in neuronal development and disease,along with their transcriptional changes under SUMOylation.Across three species,lysine is the conserved residue for SUMOylation.In Drosophila,SUMOylation of Sox N plays a repressive role in transcriptional activity,which impairs central nervous system development.However,de SUMOylation of Sox E and Sox11 plays neuroprotective roles,which promote neural crest precursor formation in Xenopus and retinal ganglion cell differentiation as well as axon regeneration in the rodent.We further discuss a potential translational therapy by SUMO site modification using AAV gene transduction and Clustered regularly interspaced short palindromic repeats-Cas9 technology.Understanding the underlying mechanisms of Sox SUMOylation,especially in the rodent system,may provide a therapeutic strategy to address issues associated with neuronal development and neurodegeneration.展开更多
Small ubiquitin-like modifiers(SUMOs)are protein modifiers that can form polymeric chains.They are important signals in cellular processes,and their study and profiling require the development of molecular tools.Herei...Small ubiquitin-like modifiers(SUMOs)are protein modifiers that can form polymeric chains.They are important signals in cellular processes,and their study and profiling require the development of molecular tools.Herein,the authors have reported an efficient chemical protein synthesis approach for the generation of dimeric SUMO-2-based photoaffinity probes through the ligation of four readily synthesizable peptides.Proteomic studies using this diSUMO-2 probe on HeLa cell nuclear lysate found it to capture a significantly different selection of proteins compared with its monoSUMO counterparts.This resulted in the identification of several previously unknown SUMO chain-specific interacting proteins such as 40S ribosomal protein S3,which showed a significantly higher affinity for polySUMO chains than monomeric SUMO.Collectively,these results emphasize the need to develop SUMO chain-based probes in other species,and to shed light on the important role of polySUMOylation in diseases.展开更多
基金Acknowledgments This study was funded by the National Natural Science Foundation of China （81570323, 30972709, 81061120527, 81241082） and the 12th Five-Year National Program of the Ministry of Scientific Technology （2012BAI10B01）. We thank Liu M and Zhou L from Beijing Hospital for providing experimental data, the nurses from Beijing Anzhen Hospital for collecting specimens, and the study volunteers.
文摘Background The genes encoding adiponectin receptor 1 （ADIPOR1） and small ubiquitin-like modifier 4 （SUM04） have been linked to anti-atherogenic effects, but little is known about whether polymorphisms in the two genes, acting separately or interacting, affect risk of coronary artery disease （CAD） without diabetes. Methods We genotyped 200 CAD patients without diabetes and 200 controls without CAD or diabetes at three single-nucleotide polymorphisms （SNPs） in ADIPOR1 and one SNP in SUM04, which were chosen based on previous studies. Potential associations were also explored between these SNPs and clinical characteristics of CAD without diabetes. Results Risk alleles at three SNPs inADIPOR1 （rs7539542-G, rs7514221-C and rs3737884-G） and the G allele at SNP rs237025 in SUM04 significantly increased risk of CAD without diabetes, with ORs ranging from 1.79 to 4.44. Carriers of any of these four risk alleles showed similar adverse clinical characteristics. Compared with individuals with a CC or GC genotype, those with a GG genotype at rs3737884 were at significantly higher risk of CAD that affected the left anterior descending coronary artery （OR： 6.77, P = 0.009）, the right coronary artery （OR： 4.81, P = 0.028） or a relatively large number of vessels （P = 0.04）. Individuals carrying a risk allele at one or more of the three SNPs in ADIPOR1 as well as a risk allele at the SNP in SUM04 were at significantly higher risk of CAD without diabetes than individuals not carrying any risk alleles （OR： 5.82, 95% CI： 1.23-27.7, P= 0.013）. Conelusions SNPs in ADIPORl and SUMO4 are associated with elevated risk of CAD without diabetes, and SNPs in the two genes may interact to jointly affect disease risk.
基金supported by the Max Planck Societythe German Research Foundation DFG (SFB 635 to G.C., and SPP 1365 and grant BA1158/3–1 to A.B.)+1 种基金the Austrian Research Foundation FWF (grant P 21215 to A.B.)pre-doctoral fellowships from the International Max Planck Research School to R.B. and R.H
文摘Small ubiquitin-like modifier （SUMO） conjugation affects a broad range of processes in plants, including growth, flower initiation, pathogen defense, and responses to abiotic stress. Here, we investigate in vivo and in vitro a SUMO conjugating enzyme with a Cys to Ser change in the active site, and show that it has a dominant negative effect. In planta expression significantly perturbs normal development, leading to growth retardation, early flowering and gene expression changes. We suggest that the mutant protein can serve as a probe to investigate sumoylation, also in plants for which poor genetic infrastructure precludes analysis via loss-of-function mutants.
文摘Small ubiquitin-like modifier(SUMO)ylation is a key posttranslational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle.
文摘Background Non-small cell lung cancer （NSCLC） is one of the most common malignant tumors.Despite the advances in therapy over the years,its mortality remains high.The aim of this study was to evaluate the expression of small ubiquitin-like modifier （SUMO） proteases 1 （SENP1） in NSCLC tissues and its role in the regulation of vascular endothelial growth factor （VEGF） expression.We also investigated the association between the expression level of SENP1 and the clinicopathological features and survival of the patients.Methods A SENP1 small interfering RNA （siRNA） was constructed and transfected into the NSCLC cells.VEGF gene expression was analyzed by real-time polymerase chain reaction （RT-PCR）.Immunohistochemistry staining was used to assess the expression of SENP1 in 100 NSCLC patients and its association with the clinicopathological features and survival was analyzed.Results VEGF expression was significantly higher in NSCLC tissues than in normal lung tissues.Inhibition of SENP1 by siRNA was associated with decreased VEGF expression.SENP1 was over-expressed in 55 of the 100 NSCLC samples （55％） and was associated with a moderate and low histological tumor grade （3.6％,38.2％,and 58.2％ in high,moderate and low differentiated tumors,respectively,P=0.046）,higher T stage （10.9％ in T1,and 89.1％ in T2 and T3 tumor samples,P ＜0.001）and TNM stage （10.9％ in stage Ⅰ,and 89.1％ in stages Ⅱ and Ⅲ tumor samples,P ＜0.001）.The rate of lymph node metastasis was significantly higher in the SENP1 over-expression group （76.4％） than that in the SENP1 low expression group （33.3％,P ＜0.001）.Sixty three patients received postoperative chemotherapy,including 34 with SENP1 over-expression and 29 with SENP1 low expression.Among the 34 patients with SENP1 over-expression,22 （64.7％） patients developed recurrence or metastasis,significantly higher than those in the low expression group 27.6％ （8/29） （P=0.005）.Multivariate Cox regression analysis showed that lymph node metastasis （P=0.015）,TNM stage （P=-0.001）,and SENP1 expression level （P=0.002） were independent prognostic factors for the survival of NSCLC patients.Conclusions SENP1 may be a promising predictor of survival,a predictive factor of chemo-sensitivity for NSCLC patients,and potentially a desirable drug target for lung carcinoma target therapy.
基金supported by Unggulan Research Grant from the Indonesian Institute of Sciences(LIPI)(Grant No.1139/F/2015)
文摘Small ubiquitin-like modifier(SUMO)-conjugating enzymes are involved in post-translational regulatory processes in eukaryotes, including the conjugation of SUMO peptides to protein substrate(SUMOylation). SUMOylation plays an important role in improving plant tolerance to abiotic stress such as salt, drought, heat and cold. Herein, we reported the isolation of OsSCE1(LOC_Os10 g39120) gene encoding a SUMO-conjugating enzyme from rice(Oryza sativa cv. Nipponbare) and its functional validation in response to drought stress. The E2 enzyme, Os SCE1, is one of three key enzymes involved in the conjugation of SUMO to its target proteins. Activated SUMO is transferred to the cysteine of an E2 enzyme and then to the target lysine residue of the substrate, with or without the help of an E3 SUMO ligase. Expression of OsSCE1 was strongly induced by polyethylene glycol 6000(PEG6000) treatment, which suggested OsSCE1 may be involved in the drought stress response. Overexpression of OsSCE1(OsSCE1-OX) in Nipponbare reduced the tolerance to drought stress. Conversely, the drought tolerance was slightly improved by the knockdown of OsSCE1(OsSCE1-KD). These results were further supported by measurement of proline content in OsSCE1-OX and OsSCE1-KD transgenic lines under induced drought stress, which showed OsSCE1-KD transgenic lines accumulated higher proline content than the wild type, whereas OsSCE1-OX line had lower proline content than the wild type. These findings suggested OsSCE1 may play a role as a negative regulator in response to drought stress in rice.
基金supported by NIH CORE Grant P30 EY08098 to the Department of Ophthalmology,University of Pittsburgh,the Eye and Ear Foundation of Pittsburgh (to KCC)。
文摘SRY-related HMG-box(Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases.Post-translational modification of Sox proteins is known to alter their functions in the central nervous system.Among the different types of post-translational modification,small ubiquitin-like modifier(SUMO) modification of Sox proteins has been shown to modify their transcriptional activity.Here,we review the mechanisms of three Sox proteins in neuronal development and disease,along with their transcriptional changes under SUMOylation.Across three species,lysine is the conserved residue for SUMOylation.In Drosophila,SUMOylation of Sox N plays a repressive role in transcriptional activity,which impairs central nervous system development.However,de SUMOylation of Sox E and Sox11 plays neuroprotective roles,which promote neural crest precursor formation in Xenopus and retinal ganglion cell differentiation as well as axon regeneration in the rodent.We further discuss a potential translational therapy by SUMO site modification using AAV gene transduction and Clustered regularly interspaced short palindromic repeats-Cas9 technology.Understanding the underlying mechanisms of Sox SUMOylation,especially in the rodent system,may provide a therapeutic strategy to address issues associated with neuronal development and neurodegeneration.
基金This study was supported by the National Key R&D Program of China(nos.2017YFA0505200 and 2017YFA0505400)the National Natural Science Foundation of China(nos.91753205,21877024,21977089,81621002,and 21621003)the Fundamental Research Funds for the Central Universities(no.JZ2019HGPB0105).
文摘Small ubiquitin-like modifiers(SUMOs)are protein modifiers that can form polymeric chains.They are important signals in cellular processes,and their study and profiling require the development of molecular tools.Herein,the authors have reported an efficient chemical protein synthesis approach for the generation of dimeric SUMO-2-based photoaffinity probes through the ligation of four readily synthesizable peptides.Proteomic studies using this diSUMO-2 probe on HeLa cell nuclear lysate found it to capture a significantly different selection of proteins compared with its monoSUMO counterparts.This resulted in the identification of several previously unknown SUMO chain-specific interacting proteins such as 40S ribosomal protein S3,which showed a significantly higher affinity for polySUMO chains than monomeric SUMO.Collectively,these results emphasize the need to develop SUMO chain-based probes in other species,and to shed light on the important role of polySUMOylation in diseases.
