MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis

Abstract

Mitochondrial antiviral signaling protein (MAVS) functions as a “switch” in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.

BAG6 negatively regulates the RLR signaling pathway by targeting VISA/MAVS

“…BAG6 facilitated the K48-linked ubiquitination of VISA may lead to inhibition of signal transduction by a failure of VISA to aggregate normally after virus Infection. However, BAG6 is not an E3 ubiquitin ligase; according to current reports, E3 ubiquitin ligases-mediated (RNF5, RNF125, MARCH5, TRIM25, AIP4) K48-linked ubiquitination initiates proteasomal degradation of VISA ( 43 , 44 ). Moreover, it’s reported that TRIM29 induced ubiquitination of Lys371, Lys420 and Lys500 sites on VISA and degradation of VISA through K11-linked polyubiquitination ( 45 ).…”

SARS‐CoV‐2 modulation of RIG‐I‐MAVS signaling: Potential mechanisms of impairment on host antiviral immunity and therapeutic approaches

“…Additionally, RIG-I-MAVS signaling is critical in the host's defense against pathogen invasion by mediating antiviral immune response. 30,[126][127][128] Host IFN-I plays a crucial role in limiting SARS-CoV-2 infection and replication, while SARS-CoV-2 may encode multiple viral proteins to counteract IFN responses, several SARS-CoV-2 proteins have been identified as IFN antagonists (Figure 6). 129 By acting on various molecules in the RIG-I-MAVS signaling pathway, SARS-CoV-2 viral proteins can evade host antiviral responses and promote viral replication.…”

“…In light of these studies, we found RIG‐I is important for vaccine or drug development against or suppression of COVID‐19 infection. Additionally, RIG‐I‐MAVS signaling is critical in the host's defense against pathogen invasion by mediating antiviral immune response 30,126–128 …”

“…Additionally, RIG‐I‐MAVS signaling is critical in the host's defense against pathogen invasion by mediating antiviral immune response. 30 , 126 , 127 , 128 …”

“…MAVS is a 540‐amino acid mitochondrion‐resident protein encoded by the nuclear genome containing an N‐terminal CARD, proline‐rich region (PRR), and C‐terminal transmembrane (TM) domain (Figure 2). 30 The TM region of MAVS is anchored to the outer membrane of mitochondria and peroxisomes, while the CARDs are located in the cytoplasm and can interact with RIG‐I/MDA5 31,32 . Normally, the two CARD domains of RIG‐I are masked by intramolecular interactions with the helicase domain, which, upon binding to viral RNA, is exposed to interact with the single CARD domain of MAVS 24,31,33,34 …”