Cystathionineγ-lyase-derived H_(2)S negatively regulates thymic egress via allosteric inhibition of sphingosine-1-phosphate lyase  

作　　者：You-tian Hu Zhi-wei Liu Tong-hui Zhang Yu-e Ma Lei He Jie Zhang Yue-yang Zhou Antonio Vidal-Puig De-jing Pan Fang Wu 

机构地区：[1]Key Laboratory of Systems Biomedicine(Ministry of Education),Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,200240,China [2]Cambridge-Suda Genomic Resource Center,Suzhou Medical College of Soochow University,Suzhou,215123,China [3]Centro de Investigacion Principe Felipe,Valencia,46012,Spain [4]Metabolic Research Laboratories,MRC Institute of Metabolic Science,University of Cambridge,Cambridge,CB20QQ,UK [5]Cambridge University Nanjing Centre of Technology and Innovation,Nanjing,210031,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2366-2379,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(32271304,31500635,21834005,31771299);Research Fund of Medicine and Engineering of Shanghai Jiao Tong University(YG2021QN144);National Key R&D Program of China(2018YFA0801100);National Center for International Research of Genomics(2017B01012).

摘　　要：Thymic egress is a crucial process for thymocyte maturation,strictly regulated by sphingosine-1-phosphate lyase(S1PL).Recently,cystathionineγ-lyase(CSE),one of the enzymes producing hydrogen sulfide(H_(2)S),has emerged as a vital immune process regulator.However,the molecular connection between CSE,H_(2)S and thymic egress remains largely unexplored.In this study,we investigated the regulatory function of CSE in the thymic egress of immune cells.We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D,L-propargylglycine(PAG)significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood,and this redistribution effect could be reversed by treatment with NaHS,an exogenous donor of H_(2)S.In addition,the CSE-generated H_(2)S significantly increased the levels of S1P in the peripheral blood,thymus and spleen of mice,suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo.Notably,H_(2)S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay.We found that this inhibition relied on a newly identified C203XC205 redox motif adjacent to the enzyme’s active site,shedding light on the biochemical mechanism of S1PL regulation.In conclusion,this study uncovers a new function and mechanism for CSE-derived H_(2)S in thymic egress and provides a potential drug target for treating S1P-related immune diseases.

关 键 词：immune cells thymic egress hydrogen sulfide S1P lyase redox motif NSC4056 

分 类 号：R36[医药卫生—病理学]