O-GlcNAcylation is an important post-translational modification and has been implicated in many fundamental cellular processes. Recent studies showed that O-linked N-acetylglucosamine （GlcNAc） transferase （OGT） me...O-GlcNAcylation is an important post-translational modification and has been implicated in many fundamental cellular processes. Recent studies showed that O-linked N-acetylglucosamine （GlcNAc） transferase （OGT） mediated O-GlcNAcylation of histone H2B Ser 112 （H2B S 112 GlcNAcylation） plays an important role in gene transcription. However, the role of this histone modification in DNA damage response has not been studied yet. In this study, we found that OGT and OGT mediated H2B S112 GlcNAcylation are involved in DNA damage response for maintaining genomic stability and are required for resistance to many DNA-damaging and replication stress- inducing agents. OGT mediated H2B Sl12 GlcNAcylation increased locally upon the induction of double-strand breaks （DSBs）, and depletion of OGT or overexpression of H2B S 112A mutant impaired homologous recombination （HR） and nonhomologous end-joining （NHEJ）. Mechanistically, H2B Sl12 GlcNAcylation could bind Nijmegen breakage syndrome 1 （NBS1） and regulate NBS1 foci for- mation. Taken together, our results demonstrate a new function of histone O-GlcNAcylation in DNA damage response （DDR）.展开更多
The aim of this present study was to explore the expression and clinical significance of O-linked N-acetylglucosamine（O-GlcNAc） transferase（OGT） and enzymatic O-linked glycosylation（O-GlcNAcation） through the ad...The aim of this present study was to explore the expression and clinical significance of O-linked N-acetylglucosamine（O-GlcNAc） transferase（OGT） and enzymatic O-linked glycosylation（O-GlcNAcation） through the addition of O-linked-β-N-acetylglucosamine in esophageal squamous cell carcinoma.OGT expression and O-GlcNAcation in 40 samples from patients with esophageal squamous cell carcinoma was detected by immunohistochemical staining with anti-OGT antib ody and O-GlcNAc-specific antibody RL 2,respectively.The relationship between pathological and clinical factors of patients was analyzed.We found that the expression of OGT was higher in esophageal squamous cell carcinoma samples compared to the normal tissues.RL 2 antibody level was positively correlated with OGT expression,and the metastasis of lymph node,which means the level of O-GlcNAcation was high and related to the metastasis of lymph node in esophageal squamous cell carcinoma.In conclusion,OGT activation is the main reason for promoting the level of O-GlcNAcation in esophageal squamous cell carcinoma.O-GlcNAcylation may play an important role in esophageal squamous cell carcinoma.展开更多
Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulat...Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.展开更多
Elevated O-GlcNAcylation has been shown to be closely correlated with the occurrence and development of cancer,and inhibiting O-GlcNAc transferase(OGT)activity was demonstrated as a potential tumor treatment strategy....Elevated O-GlcNAcylation has been shown to be closely correlated with the occurrence and development of cancer,and inhibiting O-GlcNAc transferase(OGT)activity was demonstrated as a potential tumor treatment strategy.However,the development of pharmacological OGT inhibitors still faces challenges,such as low affinity and poor selectivity.Consider-ing to OGT preferences for the sequence of its peptidic substrates,we herein integrated molecular dynamics simulation approaches to give deep insights into the binding behaviors between OGT and its peptidic substrate ZO3S1,and discussed the unfavorable inter-residue contacts inside the binding pocket,especially between H509 of OGT and S15 of the peptide,upon temperature increase.Removing this unfavorable contact from the peptide(ZO3S1 with S15A mutation)was shown to be able to increase its interaction with OGT,which was manifested by the enhanced OGT activity against this peptide.The pseudo-substrate peptide(ZO3S1 with S13A and S15A mutations)inhibited the activity of purified OGT with an IC_(50)of 192.9μM and it can also inhibit the total O-GlcNAcylation in cancer cell lines in a concentration-dependent manner.Our results provided useful models and basis for further rational optimization of selective OGT inhibitors based on the dynamic interactions of OGT and its peptidic substrates.展开更多
据《Lancet》2000年355卷第9214期报道 高雪病(Caucher s disease,一种先天性代谢障碍性疾病)的现代治疗中给予静脉内注射葡萄糖脑苷脂酶,以降低溶酶体的葡萄糖脑苷脂积蓄。降低葡萄糖脑苷脂的生物合成应减少这些基质的积蓄。英国剑桥...据《Lancet》2000年355卷第9214期报道 高雪病(Caucher s disease,一种先天性代谢障碍性疾病)的现代治疗中给予静脉内注射葡萄糖脑苷脂酶,以降低溶酶体的葡萄糖脑苷脂积蓄。降低葡萄糖脑苷脂的生物合成应减少这些基质的积蓄。英国剑桥大学医学部T.Cox教授等观察了COT918(N-butyldeoxyno-jirimycin),一种葡萄糖转换酶抑制剂。展开更多
基金supported by the grants from the National Program on Key Basic Research Project (Nos. 2013CB910300 and 2012CB910300 to H.P.)the International Science and Technology Cooperation Program of China (No. 2015DFA31680)+2 种基金the One Thousand Young Talent Program (to H.P.)the State Key Laboratory of Proteomics (No. SKLP-O201303 to C.Y.)the National Natural Science Foundation of China (No. 31371433 to H.P.)
文摘O-GlcNAcylation is an important post-translational modification and has been implicated in many fundamental cellular processes. Recent studies showed that O-linked N-acetylglucosamine （GlcNAc） transferase （OGT） mediated O-GlcNAcylation of histone H2B Ser 112 （H2B S 112 GlcNAcylation） plays an important role in gene transcription. However, the role of this histone modification in DNA damage response has not been studied yet. In this study, we found that OGT and OGT mediated H2B S112 GlcNAcylation are involved in DNA damage response for maintaining genomic stability and are required for resistance to many DNA-damaging and replication stress- inducing agents. OGT mediated H2B Sl12 GlcNAcylation increased locally upon the induction of double-strand breaks （DSBs）, and depletion of OGT or overexpression of H2B S 112A mutant impaired homologous recombination （HR） and nonhomologous end-joining （NHEJ）. Mechanistically, H2B Sl12 GlcNAcylation could bind Nijmegen breakage syndrome 1 （NBS1） and regulate NBS1 foci for- mation. Taken together, our results demonstrate a new function of histone O-GlcNAcylation in DNA damage response （DDR）.
文摘The aim of this present study was to explore the expression and clinical significance of O-linked N-acetylglucosamine（O-GlcNAc） transferase（OGT） and enzymatic O-linked glycosylation（O-GlcNAcation） through the addition of O-linked-β-N-acetylglucosamine in esophageal squamous cell carcinoma.OGT expression and O-GlcNAcation in 40 samples from patients with esophageal squamous cell carcinoma was detected by immunohistochemical staining with anti-OGT antib ody and O-GlcNAc-specific antibody RL 2,respectively.The relationship between pathological and clinical factors of patients was analyzed.We found that the expression of OGT was higher in esophageal squamous cell carcinoma samples compared to the normal tissues.RL 2 antibody level was positively correlated with OGT expression,and the metastasis of lymph node,which means the level of O-GlcNAcation was high and related to the metastasis of lymph node in esophageal squamous cell carcinoma.In conclusion,OGT activation is the main reason for promoting the level of O-GlcNAcation in esophageal squamous cell carcinoma.O-GlcNAcylation may play an important role in esophageal squamous cell carcinoma.
基金supported by the Jiangsu Provincial Medical Key Discipline(Laboratory)Cultivation Unit(JSDW202249)the Natural Science Foundation of Jiangsu Province(BK20211108)+4 种基金a Scientific Research Project of the Health Commission of Nantong(MS2023035)Nantong Natural Science Foundation(JC2023114)the Scientific Research Innovation Team of Kangda College of Nanjing Medical University(KD2022KYCXTD005)Nantong University Clinical Medicine Special Project(2022JY005)the Postgraduate Research&Practice Innovation Program of Jiangsu province(KYCX23_3416).
文摘Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.
基金supported by the National Natural Science Foundation of China(No.21907038)supported by the basic research program of Jiangnan university(No.JUSRP12016)the innovation and entrepreneurship program of Jiangsu province.
文摘Elevated O-GlcNAcylation has been shown to be closely correlated with the occurrence and development of cancer,and inhibiting O-GlcNAc transferase(OGT)activity was demonstrated as a potential tumor treatment strategy.However,the development of pharmacological OGT inhibitors still faces challenges,such as low affinity and poor selectivity.Consider-ing to OGT preferences for the sequence of its peptidic substrates,we herein integrated molecular dynamics simulation approaches to give deep insights into the binding behaviors between OGT and its peptidic substrate ZO3S1,and discussed the unfavorable inter-residue contacts inside the binding pocket,especially between H509 of OGT and S15 of the peptide,upon temperature increase.Removing this unfavorable contact from the peptide(ZO3S1 with S15A mutation)was shown to be able to increase its interaction with OGT,which was manifested by the enhanced OGT activity against this peptide.The pseudo-substrate peptide(ZO3S1 with S13A and S15A mutations)inhibited the activity of purified OGT with an IC_(50)of 192.9μM and it can also inhibit the total O-GlcNAcylation in cancer cell lines in a concentration-dependent manner.Our results provided useful models and basis for further rational optimization of selective OGT inhibitors based on the dynamic interactions of OGT and its peptidic substrates.
文摘据《Lancet》2000年355卷第9214期报道 高雪病(Caucher s disease,一种先天性代谢障碍性疾病)的现代治疗中给予静脉内注射葡萄糖脑苷脂酶,以降低溶酶体的葡萄糖脑苷脂积蓄。降低葡萄糖脑苷脂的生物合成应减少这些基质的积蓄。英国剑桥大学医学部T.Cox教授等观察了COT918(N-butyldeoxyno-jirimycin),一种葡萄糖转换酶抑制剂。
