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 innate immune signalling downstream of RNA sensing by RIG-I/MDA-5. In human and mouse cells lacking Spir-1, IRF3 and NF-κB-dependent gene activation is impaired, whereas Spir-1 overexpression enhanced IRF3 activation. Furthermore, 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 in Spir-1 KO cells. 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 the host antiviral responses.
Highlights
Infection of cells by viruses is sensed by host molecules called pattern recognition receptors (PRRs) that activate signalling pathways leading to an anti-viral response
Spir-1 is known to regulate the assembly of actin filaments inside cells, but here we show that Spir-1 functions to activate the host response to virus infection and to limit the replication and spread of both RNA and DNA viruses
The host innate immune response to viral infection begins with the sensing of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), such as Toll-like receptors and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) [1,2]
Summary
The host innate immune response to viral infection begins with the sensing of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), such as Toll-like receptors and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) [1,2]. The sensing of virus macromolecules, such as viral DNA or RNA, by PRRs triggers signalling cascades that culminate in the activation of the transcriptional factors interferon regulatory factor (IRF) 3, activator protein (AP) 1 and nuclear factor kappa B (NF-κB) [3] These transcriptional factors translocate to the nucleus where they induce the transcription of genes encoding interferons (IFN), cytokines and chemokines. Some cellular pathways, such as those leading to activation of IRF3 or NF-κB, or the JAK-STAT pathway downstream of IFNs binding to their receptors, are targeted by multiple different VACV proteins Some of these viral antagonists are multifunctional and inhibit more than one host innate immune pathway [9]
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