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Published on: December 26, 2020
Organelle-specific signaling of cGAS-STING
Shengduo Liu1, Ailian Wang2, Chen Chen2
1Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 311215, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Abstract:
Innate immune sensing through cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) surveils cytosolic DNA from invading pathogens or damaged organelles and initiates a spectrum of immune responses. It is well established that upon 2'3'-cyclic GMP-AMP (cGAMP) binding, STING exits the endoplasmic reticulum (ER), traverses the Golgi to trigger interferon programs, and finally reaches lysosomes for signal resolution through degradation, revealing a tightly choreographed itinerary for cytokine-driven immunity. However, emerging studies reveal additional layers of spatiotemporal complexity: ER-resident STING tunes in messenger RNA translation and Ca2+ efflux, Golgi-localized STING functions as a proton channel that initiates H+-dependent autophagy and transcription factor EB-directed programs for organelle homeostasis, and various mechanisms for metabolic remodeling and cell fate determination. This review synthesizes emerging organelle-specific mechanisms of cGAS-STING, delineates their roles in physiology and disease, and discusses how an organelle-centric perspective may inform selective, context-sensitive immunotherapies.
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