Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation

doi:10.1016/j.immuni.2021.02.003

	Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation
	Wang, Yan 1; Fu, Zunyun 2,3; Li, Xutong 2; Liang, Yinming 4; Pei, Siyu 1; Hao, Shumeng 1; Zhu, Qingchen 1; Yu, Tao 1; Pei, Yifei 1; Yuan, Jia 1; Ye, Jialin 1; Fu, Jiemeng 1; Xu, Jing 1; Hong, Jin 1,5; Yang, Ruirui2,6,7 ; Hou, Hui 2; Huang, Xinfang 8; Peng, Chao 9; Zheng, Mingyue 2; Xiao, Yichuan 1
	2021
发表期刊	IMMUNITY (IF:25.5[JCR-2023],33.2[5-Year])
ISSN	1074-7613
EISSN	1097-4180
卷号	54 期号:4 页码:632-+
DOI	10.1016/j.immuni.2021.02.003
摘要	Aging is associated with DNA accumulation and increased homeostatic proliferation of circulating T cells. Although these attributes are associated with aging-related autoimmunity, their direct contributions remain unclear. Conventionally, KU complex, the regulatory subunit of DNA-dependent protein kinase (DNA-PK), together with the catalytic subunit of DNA-PK (DNA-PKcs), mediates DNA damage repair in the nucleus. Here, we found KU complex abundantly expressed in the cytoplasm, where it recognized accumulated cytoplasmic DNA in aged human and mouse CD4(+) T cells. This process enhanced T cell activation and pathology of experimental autoimmune encephalomyelitis EAE) in aged mice. Mechanistically, KU-mediated DNA sensing facilitated DNA-PKcs recruitment and phosphorylation of the kinase ZAK. This activated AKT and mTOR pathways, promoting CD4(+) T cell proliferation and activation. We developed a specific ZAK inhibitor, which dampened EAE pathology in aged mice. Overall, these findings demonstrate a KU-mediated cytoplasmic DNA-sensing pathway in CD4(+) T cells that potentiates aging-related autoimmunity.
收录类别	SCIE
语种	英语
WOS研究方向	Immunology
WOS类目	Immunology
WOS记录号	WOS:000640102800007
出版者	CELL PRESS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126519
专题	生命科学与技术学院_博士生免疫化学研究所
通讯作者	Zheng, Mingyue; Xiao, Yichuan
作者单位	1.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Tissue Microenvironm & Tumor, Shanghai 200031, Peoples R China; 2.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr,State Key Lab Drug Re, Shanghai 201203, Peoples R China; 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China; 4.Xinxiang Med Univ, Sch Lab Med, Xinxiang 453003, Henan, Peoples R China; 5.Shanghai Jiao Tong Univ, Ruijin Hosp, Comprehens Breast Hlth Ctr, Sch Med, Shanghai 200025, Peoples R China; 6.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 200031, Peoples R China; 7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China; 8.Tongji Univ, Shanghai East Hosp, Sch Med, Dept Rheumatol, Shanghai 200120, Peoples R China; 9.Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Wang, Yan,Fu, Zunyun,Li, Xutong,et al. Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation[J]. IMMUNITY,2021,54(4):632-+.
APA	Wang, Yan.,Fu, Zunyun.,Li, Xutong.,Liang, Yinming.,Pei, Siyu.,...&Xiao, Yichuan.(2021).Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation.IMMUNITY,54(4),632-+.
MLA	Wang, Yan,et al."Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation".IMMUNITY 54.4(2021):632-+.