MAVS, also known as mitochondrial antiviral signaling protein, is a pivotal adaptor in the antiviral innate immune signaling pathway. It functions downstream of RIG-I-like receptors (RLRs), transducing signals to induce type I interferons (IFNs) and other antiviral molecules, thus playing a crucial role in the activation of antiviral defenses [2,5].

Lactate, a key metabolite of glycolysis, binds directly to the transmembrane domain of MAVS, preventing its aggregation and inhibiting RLR-mediated IFN production [1]. In pharmacological and genetic approaches, inactivation of lactate dehydrogenase A (LDHA) reduces lactate, heightening type I IFN production and protecting mice from viral infection, revealing a role of MAVS as a lactate sensor connecting energy metabolism and innate immunity. Phosphorylation of MAVS by kinases IKK and/or TBK1 in response to stimulation recruits and activates IRF3, which is an essential mechanism for activating the type I IFN pathway [2]. Palmitic acid (PA) enhances the innate immune response by inducing MAVS palmitoylation, aggregation, and activation, while APT2 de-palmitoylates MAVS, inhibiting antiviral signaling. Inhibitors of APT2, like ML349, can reverse MAVS activation during antiviral infections [3]. Protein arginine methyltransferase 9 (PRMT9) directly targets MAVS, methylating it at Arg41 and Arg43. This modification inhibits MAVS aggregation and auto-activation in the resting state. Upon virus infection, PRMT9 dissociates from the mitochondria, allowing MAVS to aggregate and activate [4].

In conclusion, MAVS is central to the antiviral innate immune response. Its functions are intricately regulated by various mechanisms such as metabolite binding, phosphorylation, palmitoylation, and methylation. Studies using pharmacological and genetic approaches, which can be considered as in-vivo functional studies mimicking gene knockout-like scenarios, have revealed its role in viral infection and the connection between energy metabolism and innate immunity, offering potential therapeutic strategies for viral diseases and related immune-related disorders [1-4].