An Internally Translated MAVS Variant Exposes Its Amino-

Terminal TRAF-Binding Motifs to Deregulate Interferon Induction

Minassian A, Zhang J, He S, Zhao J, Zandi E, Saito T, Liang C, Feng P.

2015. PLoS Pathog 11:e1005060.

Speaker: Wei-Sheng Chen (陳維昇)             )           Time: 15:10~16:00, November 4, 2015

Commentator: Dr. Pin Ling (凌斌 老師)         )       Place: Room 601

Abstract:

               The mitochondrial antiviral signaling (MAVS) is a mitochondrial outer membrane protein functioning as the adaptor protein of retinoic acid-inducible gene (RIG-I)-like receptors (RLRs). During virus infection, cytosolic viral RNA is recognized by RLRs, which then activates MAVS and recruits various signaling molecules to transduce downstream pathways by activating the transcription factors IRF and NF-κB. However, whether MAVS-mediated IRF and NF-κB activation can be regulated respectively upon virus infection still await (1, 2). Previously, the gamma herpesvirus proteins vGATs trigger RIG-I/MAVS signaling but selectively activate NF-κB and cast aside IRF (3). In this study, the authors found that RIG-I/MAVS-mediated interferon induction signaling can be downregulated by an endogenous MAVS variant of ~50 kDa (MAVS50). By lacking of the N-terminal caspase recruitment domain (CARD), MAVS50 selectively activates NF-κB but not IRF. In addition, MAVS50 physically interacts with full-length MAVS (MAVS70), and the competition among MAVS50, TRAF2 and TRAF6 to interact with MAVS70 results in the inhibition of MAVS70-dependent NF-κB and IRF activation. In short, the oligomers containing MAVS70 and MAVS50 selectively activate NF-κB but not IRF-IFN signaling. Furthermore, MAVS50 mutants that ablating TRAF-binding ability failed to inhibit IFNb gene expression in response to SeV infection, and could not promote VSV replication. In summary, this study provides an important insight in the mechanism of selective innate immune activation by a truncated protein and it could be a target for antiviral therapy.

References:

1.     Feng P, Moses A, Früh K. 2013. Evasion of adaptive and innate immune response mechanisms by γ-herpesviruses. Current opinion in virology 3:285-295.

2.     Hiscott J, Nguyen TLA, Arguello M, Nakhaei P, Paz S. 2006. Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses. Oncogene 25:6844-6867.

3.     Kolakofsky D, Garcin D. 2015. γHV68 vGAT: A Viral Pseudoenzyme Pimping for PAMPs. Molecular Cell 58:3-4.