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Chapter 4 : Mitochondrial Antiviral Signaling
Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology
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This chapter discusses one's current knowledge of the properties of mitochondrial antiviral signaling (MAVS), its role in signaling, as well as its role in the in vivo host response to infection with RNA viruses. MAVS was discovered independently by four different groups, and so it is also called IPS-1, VISA, and Cardif. Importantly, the mitochondrial localization of MAVS is critical for it to induce interferons I (IFN-I). The chapter provides a more detailed description of tumor receptor associated factor (TRAF) and their role in the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation associated gene 5 (MDA-5) pathway. The mitochondrial localization of MAVS is crucial for antiviral signaling because removal of the C-terminal mitochondrial targeting domain (TM) of MAVS abolishes its ability to induce IFNs. The chapter summarizes the current knowledge of MAVS signaling, and points out some outstanding questions that demand further dissection. In summary, an outline that emerges from the recent studies is that MAVS activates IKB kinase (IKK) and TBK1 through TRAF proteins as well as several kinase adaptors. To date, two studies have examined the activation of adaptive immune parameters in MAVS-/- mice. It is now well established that MAVS serves as an essential signaling adaptor in the cytosolic antiviral signaling pathway.
Mammalian immune systems employ TLRs and RLRs in order to detect viral nucleic acids. TLRs 3, 7/8, and 9 bind to viral dsRNA, ssRNA, and CpG DNA within endosomes. Upon engagement, these receptors signal through TRIF (TLR3) or MyD88 (TLR7/8 and TLR9) to activate the transcription factors NF-κB, IRF3/7, and ATF-2/c-Jun. These activated factors enter the nucleus and induce the transcription of antiviral genes including IFN-β. Alternatively, viral dsRNA and uncapped 5′-triphosphate RNA in the cytosol are detected by the RNA helicases (RLRs) RIG-I and MDA-5, respectively. Once bound to their ligands, these receptors transmit an activation signal to their common adaptor, MAVS, located on the mitochondrial surface. MAVS relays the signal to ultimately activate NF-κB, IRF3/7, and ATF-2/c-Jun, also resulting in antiviral gene induction.
The functional domains of MAVS. (A) The MAVS protein contains an N-terminal CARD domain, which is thought to interact with RLRs. Amino acids 103 to 173 contain an abundance of prolines termed a PRR. The C terminus contains a single-pass TM domain, which localizes the protein to the outer mitochondrial membrane with the N terminus facing the cytosol. (B) Evolutionary conservation of the MAVS CARD domain. An alignment of CARD domains of MAVS from several species reveals a high degree of evolutionary conservation of this region. (C) Evolutionary conservation of the mitochondrial TM domain of MAVS and its similarity to the TM domain of the Bcl-2 family members Bcl-2 and Bcl-xL.
MAVS transmits activation signals from RLRs to activate NF-κB and IRF3, resulting in transcription of IFN-β. RIG-I and MDA-5 bind viral RNA containing 5′-triphosphate and dsRNA, respectively, in the cytosol. The ligand-bound receptors then interact with MAVS through CARD-CARD interactions. MAVS subsequently binds to the adaptors TRAF6 and TRAF3. TRAF6 then activates the IKK complex, leading to the phosphorylation of IκB. IκB is then ubiquitinated and degraded by the proteasome, releasing NF-κB from inhibition. NF-κB translocates to the nucleus to induce genes including IFN-β. TRAF3 induces the activation of the IKK-related kinases TBK1 and IKK-ε, which, in turn, phosphorylate IRF3. Phosphorylated IRF3 forms a homodimer, which enters the nucleus to form an enhanceosome complex together with NF-κB to induce IFN-β transcription.