An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction.

Abstract

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.

• Authors: Arlet Minassian, Junjie Zhang, Shanping He, Jun Zhao, Ebrahim Zandi, Takeshi Saito, Chengyu Liang, Pinghui Feng
• Journal: PLoS pathogens (PLoS Pathog) Vol. 11 Issue 7 Pg. e1005060 (Jul 2015) ISSN: 1553-7374 [Electronic] United States
• PMID: 26221961 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Interferon Inducers
• MAVS protein, human
• NF-kappa B
• TNF Receptor-Associated Factor 2
• TNF Receptor-Associated Factor 6
• Interferons

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Amino Acid Sequence
• Humans
• Interferon Inducers (immunology)
• Interferons (metabolism)
• NF-kappa B (metabolism)
• Protein Binding (physiology)
• TNF Receptor-Associated Factor 2 (metabolism)
• TNF Receptor-Associated Factor 6 (metabolism)