Mavs-KO Mouse

MAVS, also known as mitochondrial antiviral signaling protein, is a pivotal adaptor in the RIG-I-like receptor (RLR) antiviral innate immune signaling pathway. It is essential for the activation of antiviral defenses, leading to the induction of type I interferons (IFNs) and other antiviral molecules, thus playing a crucial role in maintaining immune homeostasis [2,5,6]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

Lactate, a metabolite from glycolysis, binds directly to the MAVS transmembrane domain, preventing MAVS aggregation and thus inhibiting RLR-mediated type I IFN production. Inactivation of lactate dehydrogenase A (LDHA) to reduce lactate heightens type I IFN production and protects mice from viral infection, indicating the role of MAVS as a lactate sensor connecting energy metabolism and innate immunity [1]. Phosphorylation of MAVS by kinases IKK and/or TBK1 recruits and activates IRF3, revealing a conserved mechanism for type I IFN pathway activation [2]. Palmitic acid (PA) enhances MAVS palmitoylation, aggregation, and activation, while APT2 de-palmitoylates MAVS to inhibit antiviral signaling, suggesting potential strategies for combating viral infections [3]. Protein arginine methyltransferase 9 (PRMT9) methylates MAVS at Arg41 and Arg43 in resting cells to inhibit its aggregation and auto-activation, and dissociates from mitochondria upon virus infection to allow MAVS activation, maintaining innate immune homeostasis [4].

In summary, MAVS is crucial for antiviral innate immunity, with its functions tightly regulated by various molecular mechanisms. Studies using mouse models have revealed its role in viral infections and the connection between energy metabolism and immunity. Understanding MAVS functions provides potential therapeutic targets for viral diseases and autoimmune disorders [1,4,6].

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/