Review An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis, 2019, Mathavarajah et al

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An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis

Mathavarajah, Sabateeshan; Salsman, Jayme; Dellaire, Graham

Abstract
Type I interferons are effector cytokines essential for the regulation of the innate immunity. A key effector of the type I interferon response that is dysregulated in autoimmunity and cancer is the cGAS-STING signalling axis.

Recent work suggests that calcium and associated signalling proteins can regulate both cGAS-STING and autoimmunity. How calcium regulates STING activation is complex and involves both stimulatory and inhibitory mechanisms.

One of these is calmodulin-mediated signalling that is necessary for STING activation. The alterations in calcium flux that occur during STING activation can also regulate autophagy, which in turn plays a role in innate immunity through the clearance of intracellular pathogens. Also connected to calcium signalling pathways is the cGAS inhibitor TREX1, a cytoplasmic exonuclease linked to several autoimmune diseases including systemic lupus erythematosus (SLE).

In this review, we summarize these and other findings that indicate a regulatory role for calcium signalling in innate and autoimmunity through the cGAS-STING pathway.

Web | DOI | Cytokine & Growth Factor Reviews

 

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I have a gazillion tabs open with papers and tbh I can’t remember if this was one @jnmaciuch mentioned or something I found while going down a rabbit hole when first getting into this topic. But I couldn’t find it posted so thought it worth sharing as an overview

 

[jnmaciuch]

I can't remember if I ever brought up this specific paper but I'm glad you tagged me here because this figure reminded me of something I'd forgotten:


In healthy cells, this seems to be the main loop preventing calcium flux from leading to IFN signaling via cGAS-STING. It's mediated by phosphorylated AMPK, which was found to be abnormal in a couple small studies of muscle cells from Julia Newton's group (though these should be taken with a grain of salt due to small sample size/inclusion criteria, etc.).

Phosphorylation of AMPK was found to be downregulated during infection primarily by a specific interferon stimulated gene, TDRD7 (thread here). And this paper by the same group found that TDRD7 is dependent on STAT1 signaling. Which is part of the complex that mediates a large portion of the interferon response, but can be independently upregulated due to currently unknown epigenetic mechanisms (discussed here and here). So, long story short, if enough cells are skewed by this unknown mechanism that regulates baseline STAT1, and the downstream targets of STAT1 interfere with AMPK phosphorylation, then the cell loses the primary mechanism that prevents normal calcium flux from leading to an interferon response via STING. Theoretically, anyways.