An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction.
Activation of pattern recognition receptors and proper regulation of downstream signaling are crucial for host innate immune response. Upon infection, the NF-κB and interferon regulatory factors (IRF) are often simultaneously activated to defeat invading pathogens. Mechanisms concerning differential activation of NF-κB and IRF are not well understood. Here we report ... that a MAVS variant inhibits interferon (IFN) induction, while enabling NF-κB activation. Employing herpesviral proteins that selectively activate NF-κB signaling, we discovered that a MAVS variant of ~50 kDa, thus designated MAVS50, was produced from internal translation initiation. MAVS50 preferentially interacts with TRAF2 and TRAF6, and activates NF-κB. By contrast, MAVS50 inhibits the IRF activation and suppresses IFN induction. Biochemical analysis showed that MAVS50, exposing a degenerate TRAF-binding motif within its N-terminus, effectively competed with full-length MAVS for recruiting TRAF2 and TRAF6. Ablation of the TRAF-binding motif of MAVS50 impaired its inhibitory effect on IRF activation and IFN induction. These results collectively identify a new means by which signaling events is differentially regulated via exposing key internally embedded interaction motifs, implying a more ubiquitous regulatory role of truncated proteins arose from internal translation and other related mechanisms.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Humans, Interferon Inducers, Interferons, NF-kappa B, Protein Binding, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 6
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Humans, Interferon Inducers, Interferons, NF-kappa B, Protein Binding, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 6
PLoS Pathog.
Date: Jul. 01, 2015
PubMed ID: 26221961
View in: Pubmed Google Scholar
Download Curated Data For This Publication
193567
Switch View:
- Interactions 10