Expanding roles of cGAS-STING signaling in neuroinflammation
Weixi Feng, Abulimiti Aikedan, Subhash C. Sinha, Li Gan
Weixi Feng, Abulimiti Aikedan, Subhash C. Sinha, Li Gan
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Expanding roles of cGAS-STING signaling in neuroinflammation

Abstract

The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central mediator of cytosolic DNA–induced innate immune responses, driving the production of type I IFNs and pro-inflammatory cytokines. Beyond its canonical role in cytosolic DNA sensing, increasing attention has been directed toward the noncanonical functions of cGAS and STING, particularly within the nucleus. Recent studies implicate dysregulated cGAS-STING signaling in neurodegenerative diseases and brain aging, with a prominent contribution to glial activation–associated neuroinflammation, a hallmark of many neurological disorders. In this Review, we first summarize the molecular mechanisms underlying the canonical cGAS-STING pathway in DNA sensing and innate immune activation. We then discuss emerging noncanonical roles of cGAS in chromatin organization and RNA metabolism, drawing on insights from evolutionary conservation and protein interactome analyses. Finally, we outline the involvement of cGAS-STING signaling in diverse aspects of brain function, including glial state regulation, neuronal homeostasis, blood-brain barrier integrity, and peripheral immune surveillance, highlighting their contributions to neuroinflammation and neuropathology. We also summarize current pharmacological inhibitors targeting cGAS and STING and discuss their therapeutic potential for modulating cGAS-STING signaling to manage brain disorders.

Authors

Weixi Feng, Abulimiti Aikedan, Subhash C. Sinha, Li Gan

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Figure 1

Evolutionary diversification of the cGAS-STING pathway.

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Evolutionary diversification of the cGAS-STING pathway. (A) Evolutionary...
(A) Evolutionary timeline of cGAS across species. (B) Stepwise acquisition of cGAS functional domains. An N-terminal intrinsically disordered domain emerged in cephalochordates and promotes liquid-liquid phase separation and cytosolic retention, whereas the zinc ribbon domain arose later in vertebrates and is required for efficient DNA recognition and activation. (C) Evolution of STING signaling capacity. In vertebrates, STING acquired a C-terminal tail (CTT) that enables recruitment of TANK binding kinase 1 and interferon regulatory factor 3, driving robust type I interferon responses. This CTT-dependent signaling is absent in nonvertebrate STING homologs. The structures of cGAS and STING were downloaded from AlphaFold DB (170) and modified by ChimeraX (171). CDN, cyclic dinucleotide.