MAVS

Official Full Name

mitochondrial antiviral signaling protein

Organism

Homo sapiens

GeneID

57506

Background

This gene encodes an intermediary protein necessary in the virus-triggered beta interferon signaling pathways. It is required for activation of transcription factors which regulate expression of beta interferon and contributes to antiviral innate immunity. [provided by RefSeq, Jul 2020]

Synonyms

IPS1; VISA; IPS-1; CARDIF;

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Detailed Information

Mitochondrial antiviral signaling protein (MAVS) acts as an adaptor protein and plays an important role in regulating the host's natural immune signaling pathway. Cell pattern recognition receptors such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) recognize invading pathogens and transmit signals to MAVS, which activate NF- by stimulating downstream TBK1 complexes and IKK complexes, respectively. Signaling pathways such as κB and IRF3 activate interferon α/β expression and induce intracellular anti-infective natural immune responses. In addition to localizing mitochondria, MAVS can also be localized to peroxisomes. The different localization of MAVS in cells determines its different regulatory mechanisms in early rapid and sustained antiviral innate immunity.

MAVS is a classic "tail-anchored" membrane protein whose C-terminal transmembrane domain (TM) anchors MAVS to many organelle membrane surfaces, such as mitochondria, peroxisomes, and sub-domains of the endoplasmic reticulum (MAM). The different localization of MAVS mitochondria and peroxisomes determines their specificity in innate immune regulation. Peroxisome MAVS can trigger rapid, transient, and unstable expression of interferon-stimulated genes (ISGs). Mitochondrial MAVS can induce delayed and stable expression of ISG, so wild-type MAVS can induce rapid and stable expression of ISG.

Figure 1. Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses and apoptosis through inflammasome activation. (Zorzano, et al. 2015)

MAVS Function

MAVS plays a central role in the mediated innate antiviral response. Taking the RIG-I signaling pathway as an example, the E3 ubiquitin ligase Riplet and TRIM25 play a key role in their recognition of RNA and activation. RIG-I is activated by ubiquitination of K63 mediated by Riplet and TRIM25 (tripartite motif containing protein 25). After RIG-I multimerization, it forms a complex with TRIM25 and chaperone 14-3-3ε. The complex is called "translocon", which is transported from the cytoplasm to the inner membrane of the cell, such as mitochondrion-associated membrane (MAM) and MAVS.

MAVS is localized in different subcellular structures, and MAVS may anchor to different organelle membranes by recognizing specific lipids or proteins on the membrane to exert its antiviral function. This membrane localization property of MAVS is essential for its antiviral activity, and the MAVS transmembrane domain is removed to lose its antiviral activity. In the expression of MAVS mutant (miniMAVS) containing only the CARD domain and the TM domain, MAVS-mediated signaling can still be induced, and miniMAVS can maintain the functional properties of MAVS mitochondrial localization, oligomerization, and CARD domain adsorption. This helicase domain and C-terminal binding domain (CTD) of MAVS are essential structures for the recognition of viral RNA and activation of downstream signaling pathways.

Viral Digestion of MAVS

NS3/4A is a serine protease encoded by hepatitis C virus, which cleaves cysteine at position 508 of MAVS, and cleaves MAVS into two molecules of different sizes, making it unable to localize to mitochondria and destroy its oligomerization. The function of the downstream signal is activated to block the RLR-mediated signaling pathway. In addition to hepatitis C virus-encoded NS3/4A, hepatitis A virus-encoded 3ABC (a precursor of 3Cpro cysteinyl protease) and a hepatitis B virus-encoded X protein, HBX, cleave MAVS to block signal transduction. The study found that human coronavirus NL63 PLP protease disrupts the MAVSSTING-TBK1/IKKε complex, blocks the function of MAVS and STING in the antiviral innate immune signaling pathway, and negatively regulates host antiviral innate immunity, thereby revealing another new mechanism by which papa-like protease PLP regulates host antiviral innate immunity.

References:

Zorzano, A. , María Isabel HernándezAlvarez, David Sebastián, & Juan Pablo Muñoz. (2015). Mitofusin 2 as a driver that controls energy metabolism and insulin signaling. Antioxidants & Redox Signaling, 22(12), 1020-31.
Yoneyama, M. , Jogi, M. , & Onomoto, K. . (2016). Regulation of antiviral innate immune signaling by stress-induced rna granules. Journal of Biochemistry, mvv122.
Weinberg, S. , Sena, L. , & Chandel, N. . (2015). Mitochondria in the regulation of innate and adaptive immunity. Immunity,42(3), 406-417.

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