2. Academic Validation
  3. Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation

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

  • Immunity. 2021 Apr 13;54(4):632-647.e9. doi: 10.1016/j.immuni.2021.02.003.
Yan Wang 1,  Zunyun Fu 2,  Xutong Li 3,  Yinming Liang 4,  Siyu Pei 1,  Shumeng Hao 1,  Qingchen Zhu 1,  Tao Yu 1,  Yifei Pei 1,  Jia Yuan 1,  Jialin Ye 1,  Jiemeng Fu 1,  Jing Xu 1,  Jin Hong 5,  Ruirui Yang 6,  Hui Hou 3,  Xinfang Huang 7,  Chao Peng 8,  Mingyue Zheng 9,  Yichuan Xiao 10
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 School of Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, China.
  • 5 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
  • 6 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China; Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
  • 7 Department of Rheumatology, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai 200120, China.
  • 8 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai 201210, China.
  • 9 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: myzheng@simm.ac.cn.
  • 10 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: ycxiao@sibs.ac.cn.
PMID: 33667382 DOI: 10.1016/j.immuni.2021.02.003
Abstract

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.

Keywords

CD4(+) T cells; DNA sensing; KU complex; ZAK; aging; autoimmunity.

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  • HY-122727
    ≥98.0%, Ku 70/80 Heterodimer Protein Inhibitor
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