The actin nucleator Spir-1 is a virus restriction factor that promotes IRF3 activation

Abstract

Cellular proteins often have multiple and diverse functions. This is illustrated with protein Spir-1 that is an actin nucleator, but, as shown here, also functions to enhance IRF3 activation downstream of RNA sensing by RIG-I/MDA-5. In human and mouse cells lacking Spir-1, IRF3 activation is impaired, whereas Spir-1 overexpression enhanced IRF3 activation. Furthermore in Spir-1-/- cells, the infectious virus titres and sizes of plaques formed by two viruses that are sensed by RIG-I, vaccinia virus (VACV) and Zika virus, are increased. These observations demonstrate the biological importance of Spir-1 in the response to virus infection. Like cellular proteins, viral proteins also have multiple and diverse functions. Here, we also show that VACV virulence factor K7 binds directly to Spir-1 and that a diphenylalanine motif of Spir-1 is needed for this interaction and for Spir-1-mediated enhancement of IRF3 activation. Thus, Spir-1 is a new virus restriction factor and is targeted directly by an immunomodulatory viral protein that enhances virus virulence and diminishes IRF3 activation. Author SummaryInfection of cells by viruses is sensed by host molecules called pattern recognition receptors (PRRs) that activate signalling pathways leading to an anti-viral response. In turn, viruses express proteins that negate these host responses to mediate escape from the anti-viral response. Here, we report that protein K7 from a large DNA virus called vaccinia virus (VACV), binds to a host cell protein called Spir-1. Spir-1 is known to regulate the assembly of actin filaments inside cells, but here we show that Spir-1 also functions to activate the host response to virus infection and to limit the replication and spread of both RNA and DNA viruses. Thus, this study has uncovered new functions of cellular protein Spir-1 as an activator of innate immunity and as a restriction factor for diverse viruses. Further, it shows that Spir-1 is targeted by a virus protein during infection.