Xiang Chen

Defective DNA clearance in DNase II−/− mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II−/− mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II−/−STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II−/− mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.

Significance: Intestinal barrier plays a key role in maintaining organismal health. Here we find cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) deficiency compromises intestinal epithelial barrier and exacerbates inflammation. cGAS-deficient mice were highly susceptible to colitis-associated colon cancer (CAC) but not sporadic colon cancer. Surprisingly, the role of cGAS in this process appears to be independent of stimulator of interferon genes (STING)-induced type I interferon signaling, because mice lacking STING or type I interferon receptor were less susceptible to CAC than those lacking cGAS. cGAS but not STING is highly expressed in intestinal stem cells. These results suggest that cGAS has a unique role in protecting the intestinal epithelial barrier and preventing colon cancer development.

Keeping cGAS silent: Cells detect microbial and self-DNA in the cytosol as a danger signal that triggers immune and inflammatory responses. Paradoxically, a large fraction of a DNA-sensing enzyme called cGAS is tightly associated with the chromatin, especially during mitosis. Li et al. uncovered two mechanisms that prevent cGAS from being activated by the chromatin DNA (see the Perspective by Ablasser). First, cGAS is hyperphosphorylated as cells enter mitosis, thereby inhibiting its DNA-binding and liquid-liquid phase separation, which promotes cGAS activation. Second, chromatin-bound cGAS is unable to oligomerize, a process required for its activation. Together, these mechanisms ensure cGAS inactivation during cell division to prevent autoimmune reactions. Science , this issue p. eabc5386 ; see also p. 1204

In obesity, elevated insulin causes fatty liver by activating the gene encoding SREBP-1c, a transcription factor that enhances fatty acid synthesis. Two transcription factors, LXRα and C/EBPβ, are necessary but not sufficient for insulin induction of hepatic SREBP-1c mRNA. Here, we show that a third transcription factor, BHLHE40, is required. Immunoprecipitation revealed that BHLHE40 binds to C/EBPβ and LXRα in livers of rats that had fasted and then refed. Hepatic BHLHE40 mRNA rises rapidly when fasted rats are refed and when rat hepatocytes are incubated with insulin. Preventing this rise by gene knockout in mice or siRNAs in hepatocytes reduces the insulin-induced rise in SREBP-1c mRNA. Although BHLHE40 is necessary for insulin induction of SREBP-1c, it is not sufficient as demonstrated by failure of lentiviral BHLHE40 overexpression to increase hepatocyte SREBP-1c mRNA in the absence of insulin. Thus, an additional event is required for insulin to increase SREBP-1c mRNA.