Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response
Hekang Du,
Nanyang Xiao,
Sitong Zhang,
Xueyuan Zhou,
Yangfan Zhang,
Zengzeng Lu,
Yuqian Fu,
Miaohui Huang,
Shan Xu,
Qi Chen
Affiliations
Hekang Du
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Nanyang Xiao
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China; Department of Microbiology, University of Chicago, Cummings Life Science Center, 920 East 58th Street, Chicago, IL 60637, USA
Sitong Zhang
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Xueyuan Zhou
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Yangfan Zhang
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Zengzeng Lu
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Yuqian Fu
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Miaohui Huang
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Shan Xu
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China
Qi Chen
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China; Corresponding author
Summary: TREX1 encodes a major DNA exonuclease and mutations of this gene are associated with type I interferonopathies in human. Mice with Trex1 deletion or mutation have shortened life spans accompanied by a senescence-associated secretory phenotype. However, the contribution of cellular senescence in TREX1 deficiency-induced type I interferonopathies remains unknown. We found that features of cellular senescence present in Trex1−/− mice are induced by multiple factors, particularly DNA damage. The cGAS-STING and DNA damage response pathways are required for maintaining TREX1 deletion-induced cellular senescence. Inhibition of the DNA damage response, such as with Checkpoint kinase 2 (CHK2) inhibitor, partially alleviated progression of type I interferonopathies and lupus-like features in the mice. These data provide insights into the initiation and development of type I interferonopathies and lupus-like diseases, and may help inform the development of targeted therapeutics.
