Regulation and Consequences of cGAS Activation by Self-DNA

Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major responder to the pathogenic DNA of viruses and bacteria. Upon DNA binding, cGAS becomes enzymatically active to generate the second messenger cGAMP, leading to activation of inflammatory genes, type I interferon production, autophagy, and cell death. Following genotoxic stress, cGAS can also respond to endogenous DNA, deriving from mitochondria, endogenous retroelements, and chromosomes to affect cellular signaling, secretion, and cell fate decisions. However, under unperturbed conditions, signaling from self-DNA is largely, but not completely, inhibited. Here we review how endogenous DNA is exposed to cGAS, how signaling is attenuated but activated under pathological conditions, and how low-level signaling under unperturbed conditions might prime antipathogenic responses.

Keywords: STING; cGAS; genome integrity; inflammatory signaling; self-DNA.

Figure 1.. The cGAS pathway.

Classically, cGAS is stimulated by DNA from viruses and bacteria, but self-DNA such as chromosomal DNA or mitochondrial DNA can also stimulate it. Upon DNA binding, cGAS becomes enzymatically active and produces a second messenger, cyclic GMP-AMP (cGAMP). In turn, cGAMP binds and activates STING. This can promote autophagy, but also activates the inflammatory proteins kinases IKK and TBK1. This causes activation of NFkB and IRF3 in order to stimulate transcription of inflammatory genes. IRF3 also has a second, less well-defined activity that leads to apoptosis.

Figure 2:. Sources of self-DNA for cGAS activation.

(A and B) Mitochondrial DNA. (A) Mitochondrial damage can lead to release of mitochondrial DNA (mtDNA). (B) A key event in apoptosis is mitochondrial outer membrane permeabilisation (MOMP), mediated by pores generated by the proteins Bax and Bak. These can expand to form macropores, through which the inner mitochondrial membrane can herniate. By hitherto unknown mechanisms, this can lead to release of mtDNA, and/or and influx of cGAS. (C) DNA of endogenous retroelements. If loss of silencing of endogenous retroelements occurs, their reverse transcription can lead to cytoplasmic DNA that can activate cGAS. (D – F) Chromosomal DNA. (D) Following mitotic nuclear envelope disassembly, cGAS quantitatively associates with chromosomes. (E) The nuclear envelope can sometimes break locally during interphase. This results in influx of cGAS. (F) DNA damage and chromosome missegregation can result in the formation of micronuclei, which assemble nuclear envelopes that are prone to rupture and enrichment of cGAS. Note that DNA damage may also generate other DNA fragments that may activate cGAS.

Figure 3:. Consequences of cGAS activation by self-DNA.

(A) Chromosome missegregation, DNA damage, and telomere attrition can lead to induction of inflammatory genes that – at least in part – depends on cGAS. Note that a possible structure that might be responsible for cGAS activation in all these cases could be micronuclei. If telomere attrition occurs in the absence of p53, this can lead to continued proliferation, but eventually causes a cGAS-dependent upregulation of autophagy that promotes cell death. (B) During mitotic arrest, cGAS signalling builds up and eventually promotes apoptosis.