The matrix protein of rabies virus binds to RelAp43 to modulate NF-κB-dependent gene expression related to innate immunity.

Youcef Ben Khalifa,Benoit Besson,Florence Larrous,Florian Sonthonnax,Sophie Luco,Hervé Bourhy,Medhi Archambaud,Jonathan M Grimes

doi:10.1038/srep39420

Abstract

The matrix (M) protein of wild isolates of rabies virus such as Tha (M-Tha) was previously shown to be able to interact with RelAp43, a protein of the NF-κB family, and to efficiently suppress NF-κB-dependent reporter gene expression, in contrast with the vaccine strain SAD. Here, we analyze the mechanisms involved in RelAp43-M protein interaction. We demonstrate that the central part of M-Tha, and the specific C-terminal region of RelAp43 are required for this interaction. Four differences in the corresponding amino acid sequences of the M-Tha and M-SAD are shown to be crucial for RelAp43 interaction and subsequent modulation of innate immune response. Furthermore, the capacity of M-Tha to interact with RelAp43 was shown to be crucial for the control of the expression of four genes (IFN, TNF, IL8 and CXCL2) during viral infection. These findings reveal that RelAp43 is a potent regulator of transcription of genes involved in innate immune response during rabies virus infection and that the M protein of wild isolates of rabies virus is a viral immune-modulatory factor playing an important role in this RelAp43-mediated host innate immunity response in contrast to M protein of vaccine strains, which have lost this property.

Highlights

The innate immune response to virus infection involves activation of pattern recognition receptors (PRR) and transcriptional induction of many pro-inflammatory cytokines, including type I interferons (IFNs)
We showed that M-Tha was specificaly interacting with RelAp43 while neither RelA nor the conserved Rel Homology Domain (RHD) of both proteins could interact with M-Tha[1]
The data presented here confirmed that the M protein, one of the five proteins of lyssaviruses, the agents of rabies, is a potent regulator of the NF-κBsignaling

Summary

Introduction

The innate immune response to virus infection involves activation of pattern recognition receptors (PRR) and transcriptional induction of many pro-inflammatory cytokines, including type I interferons (IFNs). This activation of gene expression is controlled by the activities of some regulatory factors, such as interferon-regulatory factors 3 and 7 (IRF-3 and -7 respectively), activator protein 1 (AP1) and a family of proteins called nuclear factor of the kappa light chain enhancer of B cells (NF-κB). The ability of the M protein of lyssavirus to interact with RelAp43 and to inhibit the induction of IFN-β, providing a means to evade the anti-viral innate immunity, is lost in vaccinal strains[1]

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Results

Conclusion