cGAS-STING signaling and function in metabolism and kidney diseases

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway senses the presence of cytosolic DNA and,in turn,triggers downstream signaling to induce the expression of inflammatory and type I interferon genes in immune cells.Whereas the innate immune function of the cGAS-STING pathway is well studied over the past years,emerging evidence suggests that this signaling pathway may have additional functions beyond innate immune surveillance.Consistent with this notion,dysregulation of the cGAS-STING signaling pathway in adipocytes,hepatocytes,and renal proximal tubule epithelial cells are associated with metabolic dysfunction,impaired energy homeostasis,and kidney diseases.In this review,we summarize current understanding of the cGAS-STING pathway in several metabolic diseases such as obesity,insulin resistance,alcoholic and nonalcoholic fatty liver diseases,as well as acute kidney injury and chronic kidney disease.We also review the interaction between the cGAS-STING pathway and lipid metabolism.Lastly,we discuss potential mechanisms by which cGAS-STING signaling regulates metabolism and point toward future avenues of research targeting the cGAS-STING pathway as possible means to treat common metabolic disorders.

Rheb promotes brown fat thermogenesis by Notch-dependent activation of the PKA signaling pathway

Increasing brown and beige fat thermogenesis have an anti-obesity effect and thus great metabolic benefits.However,the molecular mechanisms regulating brown and beige fat thermogenesis remain to be further elucidated.We recently found that fat-specific knockout of Rheb promoted beige fat thermogenesis.In the current study,we show that Rheb has distinct effects on thermogenic gene expression in brown and beige fat.Fat-specific knockout of Rheb decreased protein kinase A(PKA)activity and thermogenic gene expression in brown adipose tissue of high-fat diet-fed mice.On the other hand,overexpression of Rheb activated PKA and increased uncoupling protein 1 expression in brown adipocytes.Mechanistically,Rheb overexpression in brown adipocytes increased Notch expression,leading to disassociation of the regulatory subunit from the catalytic subunit of PKA and subsequent PKA activation.Our study demonstrates that Rheb,by selectively modulating thermogenic gene expression in brown and beige adipose tissues,plays an important role in regulating energy homeostasis.

Nuclear cGAS: sequestration and beyond

The cyclic GMP-AMP(cGAMP)synthase(cGAS)has been identified as a cytosolic double stranded DNA sensor that plays a pivotal role in the type I interferon and inflammation responses via the STING-dependent signaling pathway.In the past several years,a growing body of evidence has revealed that cGAS is also localized in the nucleus where it is associated with distinct nuclear substructures such as nucleosomes,DNA replication forks,the double-stranded breaks,and centromeres,suggesting that cGAS may have other functions in addition to its role in DNA sensing.However,while the innate immune function of cGAS is well established,the non-canonical nuclear function of cGAS remains poorly understood.Here,we review our current understanding of the complex nature of nuclear cGAS and point to open questions on the novel roles and the mechanisms of action of this protein as a key regulator of cell nuclear function,beyond its well-established role in dsDNA sensing and innate immune response.