MAVS, also known as mitochondrial antiviral signaling protein, is a pivotal adaptor in the antiviral innate immune signaling pathway, especially in the RIG-I-like receptor (RLR) pathway [1,2,5,6]. It plays a crucial role in activating antiviral defenses by inducing type I interferons (IFNs) and other antiviral molecules, thus connecting energy metabolism and innate immunity [1,2]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In terms of regulation, lactate, a glycolysis-derived metabolite, binds directly to the MAVS transmembrane domain, preventing its aggregation and inhibiting RLR-mediated type I IFN production [1]. Pharmacological and genetic inactivation of lactate dehydrogenase A (LDHA), which reduces lactate, heightens type I IFN production and protects mice from viral infection, revealing the role of MAVS-lactate interaction in limiting RLR signaling [1]. Phosphorylation of MAVS by kinases IKK and/or TBK1 recruits interferon regulatory factor 3 (IRF3) for its phosphorylation and activation, a conserved mechanism to activate the type I IFN pathway [2]. Palmitic acid (PA) enhances innate immune response by inducing MAVS palmitoylation, aggregation, and activation, while APT2 de-palmitoylates MAVS, inhibiting antiviral signaling [3]. Protein arginine methyltransferase 9 (PRMT9) methylates MAVS at Arg41 and Arg43, inhibiting its aggregation in resting cells, and dissociates upon virus infection to allow MAVS activation [4].

In conclusion, MAVS is essential for antiviral innate immunity through its role in RLR signaling. Studies using mouse models have revealed its regulation by various factors such as metabolites, phosphorylation, and post-translational modifications, which are crucial in understanding viral infection and potentially developing strategies against viral diseases.

References:

1. Zhang, Weina, Wang, Guihua, Xu, Zhi-Gang, Li, Huiyan, Lin, Hui-Kuan. 2019. Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS. In Cell, 178, 176-189.e15. doi:10.1016/j.cell.2019.05.003. https://pubmed.ncbi.nlm.nih.gov/31155231/

2. Liu, Siqi, Cai, Xin, Wu, Jiaxi, Grishin, Nick V, Chen, Zhijian J. 2015. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. In Science (New York, N.Y.), 347, aaa2630. doi:10.1126/science.aaa2630. https://pubmed.ncbi.nlm.nih.gov/25636800/

3. Bu, Lang, Wang, Huan, Zhang, Shuishen, Cheng, Chao, Guo, Jianping. 2024. Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity. In Molecular cell, 84, 3513-3529.e5. doi:10.1016/j.molcel.2024.08.014. https://pubmed.ncbi.nlm.nih.gov/39255795/

4. Bai, Xuemei, Sui, Chao, Liu, Feng, Liu, Bingyu, Gao, Chengjiang. 2022. The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation. In Nature communications, 13, 5016. doi:10.1038/s41467-022-32628-y. https://pubmed.ncbi.nlm.nih.gov/36028484/

5. Hou, Fajian, Sun, Lijun, Zheng, Hui, Jiang, Qiu-Xing, Chen, Zhijian J. 2011. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. In Cell, 146, 448-61. doi:10.1016/j.cell.2011.06.041. https://pubmed.ncbi.nlm.nih.gov/21782231/

6. Wang, Xichen, Wang, Qingwen, Zheng, Chunfu, Wang, Leisheng. 2024. MAVS: The next STING in cancers and other diseases. In Critical reviews in oncology/hematology, 207, 104610. doi:10.1016/j.critrevonc.2024.104610. https://pubmed.ncbi.nlm.nih.gov/39746492/