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 

机构地区：[1]National Key Laboratory of Immunity and Inflammation,Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Suzhou,215123,Jiangsu,China [2]Key Laboratory of Synthetic Biology Regulatory Elements,Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Suzhou,215123,Jiangsu,China [3]School of Life Science and Technology,China Pharmaceutical University,Nanjing,211198,Jiangsu,China [4]Department of Pathogenic Microbiology and Immunology,School of Basic Medical Sciences,Xi’an Jiaotong University,Xi’an,Shaanxi,China [5]Institute of Infection and Immunity,Translational Medicine Institute,Xi’an Jiaotong University Health Science Center,Xi’an,Shaanxi,China [6]Key Laboratory of Environment and Genes Related to Diseases,Xi’an Jiaotong University,Xi’an,Shaanxi,China [7]Xi’an Key Laboratory of Immune Related Diseases,Xi’an,Shaanxi,China [8]Department of Radiotherapy and Oncology,The Second Affiliated Hospital of Soochow University,Suzhou,China [9]Department of Endocrinology,The Second Affiliated Hospital of Soochow University,Suzhou,China [10]Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center,Medical College of Soochow University,Suzhou,Jiangsu,China [11]Hubei Key Laboratory of Cell Homeostasis,College of Life Sciences,TaiKang Center for Life and Medical Sciences,The Institute for Advanced Studies,Frontier Science Center for Immunology and Metabolism,Wuhan University,Wuhan,China [12]Institute of Biology and Medical Sciences(IBMS),Soochow University,Suzhou,215123,Jiangsu,China

出　　处：《Cellular & Molecular Immunology》2023年第10期1232-1250,共19页中国免疫学杂志（英文版）

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.

摘　　要：SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,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 death.Furthermore,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 subset.We 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 receptorαandβchains.Mechanistically,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 IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,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.

关 键 词：T-cell homeostasis Endoplasmic reticulum-associated degradation ER stress response PERK IRE1a 

分 类 号：R392[医药卫生—免疫学]