REDD1 regulates the cGAS-STING signaling pathway in adipocytes

Mitochondria are regulators at the interface between metabolism and immunity in adipocytes. In addition to maintaining metabolic homeostasis, mitochondria control immune responses through the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. This pathway is a central component of the innate immune system for detecting cytosolic DNA and initiating immune responses. The stress-response protein REDD1 (Regulated in Development and DNA damage response 1) has been described as a regulator of mitochondria-associated membranes and may modulate mitochondrial functions. However, the role of REDD1 in controlling mitochondrial integrity and cGAS–STING signaling in adipocytes remains unclear. We showed that REDD1 expression knockdown increased the ER-mitochondria contacts, mitochondrial enlargement and cytosolic mitochondrial DNA release in 3T3-L1 adipocytes. The downregulation of REDD1 expression increased cGAS and STING protein levels through oxidative stress- and mTORC1 dependent pathways. However, increase in cGAS/STING protein expression is uncoupled from canonical inflammatory and autophagy pathways. Instead, decrease in REDD1 expression reduced fatty acid desaturase 2 (FADS2) expression, a key enzyme in polyunsaturated fatty acid metabolism in a STING-dependent manner. In conclusion, our study identifies REDD1 as a novel regulator of mitochondrial homeostasis and cGAS-STING signaling in adipocytes, potentially linking mitochondrial stress to FADS2 protein expression.