STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy

  • Cell Rep. 2026 Jun 23;45(6):117515. doi: 10.1016/j.celrep.2026.117515.
Ze-Bo Huang  1 ,  Jin-Yi Lin  1 ,  Ling-Jun Cheng  1 ,  Yong Wu  1 ,  Xiang-Zheng Gao  2 ,  Yichi Zhang  2 ,  Guan-Lin He  1 ,  He-Yu Ling  1 ,  Hayden Weng Siong Tan  3 ,  Yuxiong Guo  4 ,  Chuang Wang  5 ,  Haihe Wang  6 ,  Evandro F Fang  7 ,  Han-Ming Shen  2 ,  Guang Lu  8
Affiliations
  • 1. Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 2. Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau 999078, China.
  • 3. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
  • 4. Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 5. School of Basic Medical Science, Health Center, Ningbo University, Ningbo 315211, China.
  • 6. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 7. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway.
  • 8. Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: [email protected].
PMID: 42268710 DOI: 10.1016/j.celrep.2026.117515
Abstract

The Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical Autophagy independent of its immune function, its role in selective Autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of Mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during Mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs Mitophagy, which switches cellular response from Mitophagy to Apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.

Keywords
CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy.
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