Fig. 3.

RLR signaling activation-mediated IR. RLR signaling activation involves the recognition of cytosolic RNA via RIG-1 and MDA5. During homeostasis, LGP2 is bound to the MAVS in the microsome. LGP2 moves to mitochondria upon viral infection, leaving MAVS free in the microsome. Thus, upon recognizing cytosolic RNA, RIG-1 and MDA5 interact with MAVS, which directly interacts with the oligomerized mitochondrial PGAM5. The RIG-1 and MDA5 interaction with MAVS interacting with oligomerized PGAM5 is critical for the downstream TBK1 and IRF3 phosphorylation-mediated type 1 IFN release. IRF3 activation occurs at the ER. The RIG-1 and MDA5 activation suppress glycolysis and the TCA cycle. Instead of glycolysis, cellular glucose undergoes PPP and HBP to generate type III and IFNs. Furthermore, glycolysis via increased lactate accumulation suppresses MAVS activity through binding to its TM domains. TLR3 activation also activates MAVS.