SEL1L preserves CD8^(+) T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis

作     者：Yafeng Gao Wenhui Li Zhenghao Wang Cangang Zhang Yaping He Xiaowei Liu Kexin Tang Weiguo Zhang Qiaoming Long Yong Liu Jinping Zhang Baojun Zhang Lianjun Zhang 

作者机构：National Key Laboratory of Immunity and InflammationSuzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou215123JiangsuChina Key Laboratory of Synthetic Biology Regulatory ElementsSuzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou215123JiangsuChina School of Life Science and TechnologyChina Pharmaceutical UniversityNanjing211198JiangsuChina Department of Pathogenic Microbiology and ImmunologySchool of Basic Medical SciencesXi’an Jiaotong UniversityXi’anShaanxiChina Institute of Infection and ImmunityTranslational Medicine InstituteXi’an Jiaotong University Health Science CenterXi’anShaanxiChina Key Laboratory of Environment and Genes Related to DiseasesXi’an Jiaotong UniversityXi’anShaanxiChina Xi’an Key Laboratory of Immune Related DiseasesXi’anShaanxiChina Department of Radiotherapy and OncologyThe Second Affiliated Hospital of Soochow UniversitySuzhouChina Department of EndocrinologyThe Second Affiliated Hospital of Soochow UniversitySuzhouChina Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources CenterMedical College of Soochow UniversitySuzhouJiangsuChina Hubei Key Laboratory of Cell HomeostasisCollege of Life SciencesTaiKang Center for Life and Medical SciencesThe Institute for Advanced StudiesFrontier Science Center for Immunology and MetabolismWuhan UniversityWuhanChina Institute of Biology and Medical Sciences(IBMS)Soochow UniversitySuzhou215123JiangsuChina 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2023年第20卷第10期

页      面：1232-1250页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学] 

基　　金：supported by the National Key R&D Program of China(2022YFA0807300) the National Natural Science Foundation of China(82271775 and 81971466) the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(BK20220049)and the CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-061,2021-I2M-1-047 and 2022-I2M-2-004).BZ was in part supported by the Innovation Capability Support Program of Shaanxi 2021TD-38.JZ was in part supported by a Translational Research Grant of NCRCH(2020ZKZC04)and the National Natural Science Foundation of China(82071765) supported by the Natural Science Foundation of China(NSFC 31900645).We thank Prof.Yonghong Wan from McMaster University,Canada,for his critical reading of the manuscript and helpful discussions 

主　　题：T-cell homeostasis Endoplasmic reticulum-associated degradation ER stress response PERK IRE1a 

摘      要：SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded ***,it remains unclear how SEL1L regulates peripheral T-cell survival and ***,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell ***,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell *** also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβ***,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or ***,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T *** addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorα***,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.