Preprint Chloride Homeostasis Regulates cGAS-STING Signaling, 2024, Morse et al.

Chloride Homeostasis Regulates cGAS-STING Signaling
Jared Morse; Danna Wang; Serena Mei; Danielle Whitham; Colby Hladun; Costel C. Darie; Herman O Sintim; Modi Wang; KaHo Leung

The cGAS-STING signaling pathway has emerged as a key mediator of inflammation. However, the roles of chloride homeostasis on this pathway are unclear. Here, we uncovered a correlation between chloride homeostasis and cGAS-STING signaling.

We found that dysregulation of chloride homeostasis attenuates cGAS-STING signaling in a lysosome-independent manner. Treating immune cells with chloride channel inhibitors attenuated 2939-cGAMP production by cGAS and also suppressed STING polymerization, leading to reduced cytokine production. We also demonstrate that non-selective chloride channel blockers can suppress the NPC1 deficiency-induced, hyper-activated STING signaling in skin fibroblasts derived from Niemann Pick disease type C (NPC) patients.

Our findings reveal that chloride homeostasis majorly affects cGAS-STING pathway and suggest a provocative strategy to dampen STING-mediated inflammation via targeting chloride channels.


Link | PDF (Preprint: BioRxiv) [Open Access]

 

Posting in relation to the thread for Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α (2024, Nature Scientific Reports)