The regulation of cGAS-STING signaling by RNA virus-derived components

Abstract

The Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) serves as a key innate immune signaling axis involved in the regulation of various human diseases. It has been found that cGAS-STING pathway can recognize a variety of cytosolic double-stranded DNA (dsDNA), contributing to cause a robust type I interferon response thereby affecting the occurrence and progression of viral infection. Accumulating evidence indicates RNA virus-derived components play an important role in regulating cGAS-STING signaling, either as protective or pathogenic factors in the pathogenesis of diseases. Thus, a comprehensive understanding of the function of RNA virus-derived components in regulating cGAS-STING signaling will provide insights into developing novel therapies. Here, we review the existing literature on cGAS-STING pathway regulated by RNA virus-derived components to propose insights into pharmacologic strategies targeting the cGAS-STING pathway.

Keywords: RNA virus-derived components; STING; Signaling pathway; cGAS.

Fig. 1

Schematic diagram of cGAS-STING signaling pathway. (cGAS, as an innate immune sensor, is able to recognize various cytoplasmic dsDNA from pathogens, apoptotic/dead cells, mitochondria, and others. The interaction between cGAS and dsDNA leads to enzymatic activation of cGAS and catalyzing the formation of 2’,3’-cyclic GMP-AMP (cGAMP) from ATP and GTP. cGAMP binds to the dimer of interferon gene stimulatory factor (STING) located on the endoplasmic reticulum (ER) membrane. Then, STING moves from the ER to Golgi body via the ER–Golgi intermediate compartment, and then serves as a signaling platform for TBK1 phosphorylation. TBK1 phosphorylates the C-terminal domains of STING, and then IRF3 is recruited and phosphorylated. Finally, dimerized IRF3 can act as a transcription factor to initiate the transcription of type-I IFN and subsequent induction of ISG expression, eliciting antiviral defense)