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. © 2015 minassian et al.