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ORIGINAL ARTICLES

Sensing of DNA double-strand breaks by the NHEJ system stabilizes RORγt transcriptional activity and shapes Th17 pathogenicity in autoimmunity

Guan-Yu Chen^1,† , Wen-Jie Zhu^1,† , Zhuang Li^1,† , Yun-Wei Hu^1,2,† , Xiao-Shuang Luo^1,† , Zhi-Qing Mai¹ , Yuan Pan¹ , Yu-Xun Shi¹ , Zuo-Yi Li¹ , Jun Huang^1,2 , Pei-Dong Yuan^1,3 , Zhi-Qiang Xiao¹ , Qian Chen^1,4 , Yan-Yan Xie¹ , Hai-Xiang Huang¹ , Yu-Xi Chen¹ , Yao Lu^1,5 , Min-Zhen Wang¹ , Yi-Wen Xia¹ , Xiao-Qing Chen^1,* , Dong-Ming Kuang^6,* , Dan Liang^1,*

¹State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
²Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
³Department of Ophthalmology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
⁴Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
⁵Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁶Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
^†These authors contributed equally: Guan-Yu Chen, Wen-Jie Zhu, Zhuang Li, Yun-Wei Hu, Xiao-Shuang Luo
* Correspondence: Xiao-Qing Chen(chenxiaoqing@gzzoc.com)Dong-Ming Kuang(kdming@mail.sysu.edu.cn)Dan Liang(liangdan@gzzoc.com)

Robust mitochondrial ROS production induces extensive double-strand breaks (DSBs) in telomeric DNA of effector T cells, where the DNA repair machinery is rapidly hyper-evoked to sense and ligate DSBs during the respiratory burst. However, whether effector T cells can exploit the DNA repair system to simultaneously potentiate their functional activation remains largely unknown, especially in the context of autoimmunity. Here, we demonstrate that non-homologous end joining (NHEJ), a predominant mechanism of DNA repair, is highly activated in pathogenic T helper 17 (pTh17) cells and exerts a previously unrecognized effect on shaping the pathogenic nature of pTh17s to trigger autoimmunity. Mechanistically, the perception of DSBs by KU proteins facilitates auto-phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which stabilizes RORγt to bind to the promoters of effector-gene loci, thus initiating the pTh17 effector program to induce autoimmunity. Using mass spectrometry and transcriptome analyses, we identified IER2 as a novel NHEJ factor that potentiates DNA-PKcs kinase activity in response to IL-23R stimulation, which is necessary for shaping Th17 pathogenicity. Therefore, targeting the immuno-pattern of the NHEJ system shows potential for the treatment of autoimmune diseases.

https://doi.org/10.1038/s41422-025-01204-6

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