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

Summary 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.