Unique nonstructural proteins of Pneumonia Virus of Mice (PVM) promote degradation of interferon (IFN) pathway components and IFN-stimulated gene proteins

Jayeeta Dhar,Sailen Barik

doi:10.1038/srep38139

Abstract

Pneumonia Virus of Mice (PVM) is the only virus that shares the Pneumovirus genus of the Paramyxoviridae family with Respiratory Syncytial Virus (RSV). A deadly mouse pathogen, PVM has the potential to serve as a robust animal model of RSV infection, since human RSV does not fully replicate the human pathology in mice. Like RSV, PVM also encodes two nonstructural proteins that have been implicated to suppress the IFN pathway, but surprisingly, they exhibit no sequence similarity with their RSV equivalents. The molecular mechanism of PVM NS function, therefore, remains unknown. Here, we show that recombinant PVM NS proteins degrade the mouse counterparts of the IFN pathway components. Proteasomal degradation appears to be mediated by ubiquitination promoted by PVM NS proteins. Interestingly, NS proteins of PVM lowered the levels of several ISG (IFN-stimulated gene) proteins as well. These results provide a molecular foundation for the mechanisms by which PVM efficiently subverts the IFN response of the murine cell. They also reveal that in spite of their high sequence dissimilarity, the two pneumoviral NS proteins are functionally and mechanistically similar.

Highlights

In previous studies, we and others reported that the NS proteins of human Respiratory Syncytial Virus (RSV), expressed in human cells, degrade multiple proteins of the IFN pathways, notably RIG-I and IRF3 of the IFN induction pathway, and the STAT2 protein of the IFN response pathway[9,18,19,21]
In the IFN response pathway, STAT2 was previously found to be the sole substrate of the RSV NS proteins; we studied the effect of Pneumonia Virus of Mice (PVM) NS proteins on recombinant mouse STAT2 in some detail
We demonstrate that despite their highly dissimilar amino acid sequences, the two nonstructural (NS) proteins of the pneumoviruses, RSV and PVM, promote degradation of multiple, albeit specific, members of the IFN pathway using the host cell’s ubiquitin-proteasome system

Summary

Introduction

We and others reported that the NS proteins of human RSV, expressed in human cells, degrade multiple proteins of the IFN pathways, notably RIG-I and IRF3 of the IFN induction pathway, and the STAT2 protein of the IFN response pathway[9,18,19,21]. We report that the NS proteins of PVM, even though their primary structures bear no similarity to the RSV counterparts (Supplementary Fig. 1), target common www.nature.com/scientificreports/. The PVM NS proteins, like the RSV counterparts, appear to promote the degradation of the IFN components by a ubiquitin-based proteasomal mechanism. The NS proteins of the two pneumoviruses, in spite of their sequence divergence, have evolved to be functionally and mechanistically homologous

Methods

Results

Conclusion