Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

Abstract

Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special asymmetric cyclic-dinucleotide, 2′3′-cGAMP, as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory genes. Hyperactivation of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune therapy. On the other hand, inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune surveillance. Thus, cGAS activation is tightly controlled. In this review, we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation, including cGAS pre- and post-translational regulations, cGAS-binding proteins, and additional cGAS regulators such as ions and small molecules. We will also reveal the pathophysiological function of cGAS and its product cGAMP in human diseases. We hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.

STING-Mediated Interferon Induction by Herpes Simplex Virus 1 Requires the Protein Tyrosine Kinase Syk

“…The ligands of STING are the various 2′,3′-linked cyclic dinucleotides produced by intracellular bacteria or cGAMP synthesized by the mammalian cytoplasmic enzyme cGAS, which is activated by cellular or microbial DNA if present in the cytoplasm ( 8 – 10 ). Many DNA viruses, such as herpes simplex virus 1 (HSV-1), trigger STING signaling, presumably due to leakage of viral DNA from the nucleus to the cytoplasm ( 11 , 12 ). STING-mediated induction of IFN inhibits HSV-1 replication, and in the absence of this negative feedback loop, the virus replicates better and is more pathogenic in mice ( 13 , 14 ).…”

Psoriasis-Associated Inflammatory Conditions Induce IL-23 mRNA Expression in Normal Human Epidermal Keratinocytes

“…In psoriasis, nucleic acid fragments originating from tissue or pathogens are present and recognized as pathogenic factors for disease development [ 15 , 17 , 19 ]. Several PRRs that recognize these RNA and DNA fragments and induce inflammatory mechanisms have already been identified [ 31 , 32 , 33 ], and many of these are expressed in both keratinocytes and professional immune cells. We aimed to examine which of these receptors plays an important role in mediating nucleic-acid-induced IL-23 mRNA expression in keratinocytes.…”

“…However, it was previously shown that poly(dA:dT) is transcribed into dsRNA by RNA polymerase III before recognition by the RIG-I receptor [ 28 , 46 ], which, as suggested previously, might explain the kinetic differences between poly(I:C) and poly(dA:dT) treatment [ 28 ]. Recently, cGAS was described as the major PRR to recognize cytosolic DNA fragments [ 32 , 33 ]. To date, the involvement of these receptors in the production of IL-23 by keratinocytes has not been addressed.…”

Structures and Dynamics of Dengue Virus Nonstructural Membrane Proteins

“…A recent study shows that NS2B alone is able to degrade cyclic GMP-AMP synthase (cGAS) in the absence of NS3 [84]. As cGAS is functional as a cytosolic DNA sensor to activate the ER host protein STING for type I interferon (IFN) signaling [85], NS2B is vital in reducing the host's innate response upon viral infection to promote viral replication and disease. The structure of the NS2B cofactor region in complex with NS3 has been thoroughly studied [34,65,66].…”