cGAS attenuates hypoxia-inducible factor signaling via chaperone-mediated autophagic degradation of HIFα

  • Cell Rep. 2026 Jun 23;45(6):117377. doi: 10.1016/j.celrep.2026.117377.
Xiong Li  1 ,  Rui Wang  1 ,  Xiaolian Cai  1 ,  Gang Ouyang  2 ,  Jun Li  1 ,  Ziyi Li  1 ,  Jing Wang  1 ,  Xing Liu  1 ,  Jian-Fang Gui  3 ,  Wuhan Xiao  4
Affiliations
  • 1. State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Hubei Hongshan Laboratory, Wuhan, P.R. China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266237, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; The Innovation of Seed Design, Chinese Academy of Sciences, Wuhan 430072, P.R. China.
  • 2. State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Hubei Hongshan Laboratory, Wuhan, P.R. China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266237, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; The Innovation of Seed Design, Chinese Academy of Sciences, Wuhan 430072, P.R. China; Hainan Seed Industry Laboratory, Sanya 572024, P.R. China.
  • 3. State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Hubei Hongshan Laboratory, Wuhan, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; The Innovation of Seed Design, Chinese Academy of Sciences, Wuhan 430072, P.R. China.
  • 4. State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Hubei Hongshan Laboratory, Wuhan, P.R. China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266237, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; The Innovation of Seed Design, Chinese Academy of Sciences, Wuhan 430072, P.R. China. Electronic address: [email protected].
PMID: 42172124 DOI: 10.1016/j.celrep.2026.117377
Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a key component of the innate immune response and initiates stimulator of interferon genes (STING)-dependent signaling in an ancient stress response. Hypoxia-inducible transcription factors 1α and 2α control the hypoxia response, another ancient stress response. This response regulates genes involved in adapting to hypoxia. We discovered that hypoxia-induced phosphatidylinositol 4,5-biphosphate (PIP2) depletion results in the relocation of cGAS from the plasma membrane, which suppresses hypoxia signaling. Mechanistically, cGAS enhances HIFα binding to HSC70/LAMP2A, thus leading to chaperone-mediated Autophagy (CMA) of HIFα. Prolonged hypoxia enhances cGAS oligomerization, which reduces the ability of cGAS to promote HIFα degradation. Disrupting cGAS in mice and zebrafish resulted in the upregulation of hypoxia-inducible genes, a change that enhanced tolerance to hypoxia. These results suggest that cGAS attenuates hypoxia signaling by promoting CMA degradation of HIFα.

Keywords
CMA; CP: cell biology; HIFα; HSC70/LAMP2A; cGAS; hypoxia.
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