A Bicistronic MAVS Transcript Highlights a Class of Truncated Variants in Antiviral Immunity

Abstract

Bacterial and viral mRNAs are often polycistronic. Akin to alternative splicing, alternative translation of polycistronic messages is a mechanism to generate protein diversity and regulate gene function. Although a few examples exist, the use of polycistronic messages in mammalian cells is not widely appreciated. Here we report an example of alternative translation as a means of regulating innate immune signaling. MAVS, a regulator of antiviral innate immunity, is expressed from a bicistronic mRNA encoding a second protein, miniMAVS. This truncated variant interferes with interferon production induced by full length MAVS, whereas both proteins positively regulate cell death. To identify other polycistronic messages, we carried out genome-wide ribosomal profiling and identified a class of antiviral truncated variants. This study therefore reveals the existence of a functionally important bicistronic antiviral mRNA, and suggests a widespread role for polycistronic mRNAs in the innate immune system.

MAVS splicing variants contribute to the induction of interferon and interferon-stimulated genes mediated by RIG-I-like receptors

“…MAVS 1a inhibits RIG-I and MAVS activity, whereas MAVS 1b displays antiviral activity against VSV infection, and selectively activates IFNβ promoter (Lad et al, 2008). In addition, the truncated variant miniMAVS interferes with IFN production induced by full-length MAVS (Brubaker et al, 2014). In salmon and mammals, a MAVS deletion mutant lacking the C-terminal TM domain abolished the ability of MAVS to protect cells against viral challenge (Biacchesi et al, 2009;Seth et al, 2005).…”

“…In mammals, three MAVS variants were isolated from human Hela 229 cells, and MAVS variants 1a and 1b containing uncharacterized sequences showed opposite effect on IFNβ expression, while variant 1c without the C-terminal TM had no activity on either NF-κB or IRF3 pathway (Lad et al, 2008); a miniMAVS, which was expressed from a second translational start site M142, was also identified in human cell lines, and the truncated variant without CARD domain interfered with IFN production induced by full-length MAVS (Brubaker et al, 2014). In teleost fish, MAVS orthologs have been reported from Japanese flounder (Paralichthys olivaceus) (Simora et al, 2010), salmon (Salmo salar) (Biacchesi et al, 2009;Lauksund et al, 2009), zebrafish (Danio rerio) (Biacchesi et al, 2009(Biacchesi et al, , 2012Xiong et al, 2012), carp (Cyprinus carpio) (Feng et al, 2011), grass carp (Ctenopharyngodon idella) (Su et al, 2011;Wan et al, 2013) and spotted green pufferfish (Tetraodon nigroviridis) (Xiang et al, 2011).…”

Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors

“…Intriguingly, recently reported that MAVS mRNA is bicistronic and codes for both full-length MAVS and a truncated variant, miniMAVS. miniMAVS inhibits MAVS-induced antiviral responses, however, both proteins positively regulate cell death (Brubaker et al 2014).…”

Innate recognition of microbial-derived signals in immunity and inflammation

“…E3 ubiquitin ligase RING finger protein 122 (RNF122) can supress RIG-I-triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I . A bicistronic mRNA of MAVS has been identified to encode a second protein miniMAVS to interfere with interferon production induced by full-length MAVS (Brubaker et al, 2014). Human OASL contributes to host antiviral responses by specifically enhancing RIG-I activation through its C-terminal ubiquitin-like domain .…”