GSE113519
Identification of Nrf2 regulated genes by RNA sequencing
The transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is activated by the metabolite  itaconate during metabolic reprogramming. Activated Nrf2 then dampens the release of pro-inflammatory  cytokines and type I IFNs in response to toll-like receptor stimulation. If and how Nrf2 affects cytosolic  antiviral sensing and whether this occurs during metabolic reprogramming is currently not known. Here, we  show that Nrf2 is a negative regulator of the adaptor molecule STimulator of INterferon Genes (STING),  which signals downstream of the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS). The regulation  of STING by Nrf2 was inducible by the metabolite itaconate, specific to human cells, and sufficient to  decrease the responsiveness to STING agonists and to increase the susceptibility to infection with DNA  viruses. Mechanistically, Nrf2 regulated STING expression post-transcriptionally by increasing STING  mRNA stability. Lastly, treatment with itaconate or with the chemical Nrf2 inducer sulforaphane repressed  STING expression and the release of type I IFNs in cells from patients with the STING dependent  interferonopathy SAVI. With this report we identify Nrf2 as an important regulator of cGAS-STING  signaling pathway and link metabolic reprogramming to control of cytosolic DNA sensing. Overall design: RNA sequencing of control and Nrf2 siRNA treated A549 cells was generated by Active Motif (Carlsbad, California, USA), in triplicate, Illumina HiSeq 4000.