MAVS

MAVS Full Name

mitochondrial antiviral signaling protein

MAVS Introduction

Mitochondrial Antiviral Signaling protein (MAVS), also known as IPS-1, VISA and Cardif, is an adaptor protein of the innate immune system. MAVS is the central and essential signaling hub in innate immune defense against virus infections. The MAVS protein consists of three functional domains: the N-terminal caspase activation and recruitment domain (CARD), the central proline-rich region (PRR) and the C-terminal transmembrane domain (TM). The C-terminal TM domain of MAVS is necessary for functional MAVS localization and tethers MAVS to the outer mitochondrial membrane (OMM). This domain is also found on the membranes of other organelles, such as peroxisomes. This unique subcellular localization is significant for MAVS-mediated signal transduction, spatially linking viral sensing and downstream signaling events, providing an efficient platform for signal amplification. The N-terminal CARD domain of MAVS is involved in homotypic and heterotypic CARD-CARD interactions, providing a basis for MAVS polymerization and recruitment of downstream molecules. The central PRR region is thought to serve as a "scaffold" binding to different signaling molecules (members of the TRAF family, for example) to fine-tune the flow and intensity of the signal.

Figure 1. Structure and function of the MAVS protein. (Source: Dong H, et al. 2024)

The primary role of MAVS is as a central mediator of RIG-I-like receptor (RLR) signaling. Recognition of invading viral RNA by cytosolic pattern recognition receptors (RIG-I, MDA5) leads to conformational changes and exposure of their own CARD domains. The activated RIG-I/MDA5 then translocate to the OMM, and through CARD-CARD interactions, activates the MAVS protein. MAVS activation is not a simple protein binding event, but rather the CARD-CARD interactions induce MAVS to polymerize and aggregate in a prion-like fashion, forming higher order, self-catalytic, and transmissible helical fibrous polymers. This newly formed large MAVS signaling complex then recruits and activates many downstream effector molecules which can be categorised into one of two main branches: one recruits TRAF3 and activates TBK1 and IKKε kinases which in turn phosphorylate and activate the transcription factors IRF3 and IRF7; the other recruits TRAF6 and activates the IKK complex which results in the activation of the NF-κB transcription factor. The now activated IRF3/7 and NF-κB translocate to the nucleus and synergistically induce the expression of type I and type III IFNs as well as many pro-inflammatory cytokines (TNF-α, IL-6). This induces a broad-spectrum antiviral state in the cell and neighbouring cells, and also initiates the adaptive immune response.

In view of the importance of MAVS in immune signaling, its aberrant activity is linked with the pathogenesis of many human diseases. With regard to autoimmune diseases, SLE is the most studied to date. The discovery that, in the PBMCs from some SLE patients, MAVS spontaneously forms prion-like aggregates that persist in the absence of viral infection has been made. This abnormal, persistent activation of MAVS leads to chronic hyperactivation of the downstream signaling pathway, causing excessive production of type I interferons. This is a key component in the pathogenesis of SLE, known as the "type I interferon signature."

Alternate Names for MAVS

MAVS; mitochondrial antiviral signaling protein; IPS1; VISA; IPS-1; CARDIF; mitochondrial antiviral-signaling protein; IFN-B promoter stimulator 1; CARD adaptor inducing IFN-beta; virus-induced signaling adaptor

• 1. Dong H, et al. MAVS Ubiquitylation: Function, Mechanism, and Beyond. Front Biosci (Landmark Ed). 2024 Feb 21;29(2):72.
  2. Chen Y, et al. MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis. Front Microbiol. 2021 Sep 9;12:744348.