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

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外文摘要：SEL1 L-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 receptor α and β chains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1I-/-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 Sel1I-/-CD8+T cells.In addition,IRE1α deficiency decreased mTORC1 signaling in Sel1 I-/-naïve CD8+T cells by downregulating the IL-15 receptor αchain.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.

外文关键词：

T-cell homeostasisEndoplasmic reticulum-associated degradationER stress responsePERKIRE1α

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

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作者单位：

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

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

School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198 Jiangsu,China

Department of Pathogenic Microbiology and Immunology,School of Basic Medical Sciences,Xi'an Jiaotong University,Xi'an,Shaanxi,China

Institute of Infection and Immunity,Translational Medicine Institute,Xi'an Jiaotong University Health Science Center,Xi'an,Shaanxi,China

Key Laboratory of Environment and Genes Related to Diseases,Xi'an Jiaotong University,Xi'an,Shaanxi,China

Xi'an Key Laboratory of Immune Related Diseases,Xi'an,Shaanxi,China

Department of Radiotherapy and Oncology,The Second Affiliated Hospital of Soochow University,Suzhou,China

Department of Endocrinology,The Second Affiliated Hospital of Soochow University,Suzhou,China

Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center,Medical College of Soochow University,Suzhou,Jiangsu,China

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

Institute of Biology and Medical Sciences(IBMS),Soochow University,Suzhou 215123 Jiangsu,China

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基金：

National Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNatural Science Foundation Outstanding Youth Fund of Jiangsu ProvinceCAMS Innovation Fund for Medical SciencesCAMS Innovation Fund for Medical SciencesCAMS Innovation Fund for Medical SciencesInnovation Capability Support Program of ShaanxiTranslational Research Grant of NCRCHNational Natural Science Foundation of ChinaNatural Science Foundation of China

项目编号：

2022YFA08073008227177581971466BK20220049CIFMS 2021-I2M-1-0612021-I2M-1-0472022-I2M-2-0042021TD-382020ZKZC0482071765NSFC 31900645

出版年：

2023

DOI：

10.1038/s41423-023-01078-x

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(10)

参考文献量52