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
刊名	IMMUNITY
	2021-04-13
卷号	54 期号:4 页码:632-+
ISSN号	1074-7613
DOI	10.1016/j.immuni.2021.02.003
通讯作者	Zheng, Mingyue(myzheng@simm.ac.cn) ; Xiao, Yichuan(ycxiao@sibs.ac.cn)
英文摘要	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.
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDB39030300] ; National Key R&D Program of China[2018YFA0107201] ; National Key R&D Program of China[2018YFA0902703] ; National Natural Science Foundation of China[82030041] ; National Natural Science Foundation of China[81770567] ; Program of Shanghai Academic/Technology Research Leader[20XD1424600] ; 111 program[D20036] ; CAS Key Laboratory of Tissue Microenvironment and Tumor
WOS关键词	DEPENDENT PROTEIN-KINASE ; GMP-AMP SYNTHASE ; CATALYTIC SUBUNIT ; EXONUCLEASE TREX1 ; DAMAGE RESPONSES ; IMMUNE-SYSTEM ; SENSOR CGAS ; PROMOTES ; REPAIR ; IDENTIFICATION
WOS研究方向	Immunology
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000640102800007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296594]
专题	中国科学院上海药物研究所
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-+.