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

Abstract

Characterisation of viral proteins that mediate immune evasion enables identification of host proteins that function in innate immunity and act as viral restriction factors. This is shown here with vaccinia virus (VACV) protein K7. K7 is a virulence factor that inhibits activation of IRF3 and NF-κB and binds the DEAD-box RNA helicase 3 (DDX3). In this study, Spir-1 is characterised as an additional cellular protein bound by K7 during VACV infection. Spir-1 belongs to a family of actin-binding proteins, however its interaction with K7 does not require its actin-binding domains, suggesting a new function. In human and mouse cells lacking Spir-1, IRF3 activation is impaired, whereas, conversely, Spir-1 overexpression enhanced IRF3 activation. Like DDX3, Spir-1 interacts with K7 directly via a diphenylalanine motif that also is required to promote IRF3 activation. The biological importance of Spir-1 in the response to virus infection is shown by enhanced replication/spreading of VACV in Spir-1 knockout cells. Thus Spir-1 is a new viral restriction factor that functions to enhance IRF3 activation.