Deamidation Shunts RelA from Mediating Inflammation to Aerobic Glycolysis

Abstract

Highlights d CAD, the rate-limiting de novo pyrimidine synthesis enzyme, deamidates RelA d Deamidation shunts RelA from mediating an inflammatory response to aerobic glycolysis d Deamidation of RelA occurs in a cell cycle-dependent manner d Cancer cells hijack RelA deamidation to promote glycolysis and tumorigenesis

Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection

“…Given that multiple SARS-CoV-2 viral polypeptides induce IRF3 deamidation, we reasoned that a cellular enzyme catalyzes IRF3 deamidation. The human genome encodes 11 glutamine amidotransferases that can potentially function as protein deamidases (Li et al, 2019; Zhao et al, 2020). With shRNA-mediated knockdown, we screened for cellular GATs, when knocked down, increase IFN induction by Sendai virus infection.…”

“…Similarly, cells may deploy this mechanism to curtail expression of genes that are not essential during proliferation when CTPS1 is highly active. Such a mechanism is analogous to the CAD-mediated RelA deamidation that shunts RelA to transactivate the expression of key glycolytic enzymes in promoting carbon metabolism during S phase (Zhao et al, 2020). SARS-CoV-2 hijacks CTPS1 to deamidate IRF3 to evade IFN induction during infection, which may explain previous observations that SARS-CoV-2 fails to induce IFN production in COVID-19 patients and in animal models (Johansen et al, 2020).…”

“…These molecules stimulate IFN induction, but not NF-κB activation. CTPS1 and CAD negatively regulate the IFN and NF-κB induction, respectively (Zhao et al, 2020). The specific stimulation of IFN induction by compound 1 and its derivative thus suggests their inhibition of CTPS1, but not CAD.…”

“…Luciferase reporter plasmids for IFN-β, NF-κB promoters, RIG-I-N, MAVS, TBK1, IRF3-5D and shRNA for human glutamine amidotransferases (CTPS1, CTPS2, GFPT1, GFPT2, GMPS, PFAS, PPAT, CPS1, ASNS and NADSYN1) were described previously (Li et al, 2019; Zhao et al, 2020; Zhao et al, 2016b). A cDNA construct was used to amplify and clone CTPS1 into mammalian expression vectors.…”

“…Our studies have shown that these enzymes are capable of deamidating key signaling molecules, such as those involved in innate immune defense, to modulate fundamental biological processes (Zhao et al, 2016a). Recent studies from our group suggest that cellular GATs potentially couple innate immune response to cellular metabolism via deamidating checkpoint proteins, e.g., RIG-I and RelA (He et al, 2015; Zhao et al, 2020; Zhao et al, 2016b).…”