Abstract
Activation of the innate immune response triggered by dsRNA viruses occurs through the assembly of the Mitochondrial Anti-Viral Signaling (MAVS) complex. Upon recognition of viral dsRNA, the cytosolic receptor RIG-I is activated and recruited to MAVS to activate the immune signaling response. We here demonstrate a strict requirement for a mitochondrial anchored protein ligase, MAPL (also called MUL1) in the signaling events that drive the transcriptional activation of antiviral genes downstream of Sendai virus infection, both in vivo and in vitro. A biotin environment scan of MAPL interacting polypeptides identified a series of proteins specific to Sendai virus infection; including RIG-I, IFIT1, IFIT2, HERC5 and others. Upon infection, RIG-I is SUMOylated in a MAPL-dependent manner, a conjugation step that is required for its activation. Consistent with this, MAPL was not required for signaling downstream of a constitutively activated form of RIG-I. These data highlight a critical role for MAPL and mitochondrial SUMOylation in the early steps of antiviral signaling.
Highlights
The first line of host defense against infection is the recognition of invading microbial pathogens or other potential threats by the cell surface Toll-like receptors that sense the presence of bacteria or viruses in the extracellular environment
The SUMO E3 ligase for retinoic acid-inducible gene I (RIG-I) was later shown to be the mitochondrial anchored protein ligase MAPL, but in that study the data suggested that SUMOylation played an inhibitory role in antiviral signaling[12]
The activation and assembly of the RIG-I/Mitochondrial Anti-Viral Signaling (MAVS) signaling pathway is known to require a host of post-translational modifications, including phosphorylation, ubiquitination and SUMOylation[1]
Summary
The first line of host defense against infection is the recognition of invading microbial pathogens or other potential threats by the cell surface Toll-like receptors that sense the presence of bacteria or viruses in the extracellular environment. MAVS is anchored within both mitochondria and peroxisomes, and upon binding to dsRNA:RIG-I complexes, assembles into a filamentous protein aggregate that recruits the TNF receptor associated factors TRAF2/6, E3 ubiquitin ligases that generate free K63 linked ubiquitin chains[1] Together this acts as a scaffold to recruit the kinases IKK or TBK1, which phosphorylate IRF3 and MAVS7. The SUMO E3 ligase for RIG-I was later shown to be the mitochondrial anchored protein ligase MAPL ( called MULAN, MUL1, GIDE, HADES), but in that study the data suggested that SUMOylation played an inhibitory role in antiviral signaling[12]. Our data demonstrate a clear role for MAPL and mitochondrial SUMOylation in the activation of RIG-I, a modification essential for the mitochondrial antiviral signaling response
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