A ΩX a V motif in the Rift Valley fever virus NSs protein is essential for degrading p62, forming nuclear filaments and virulence

Infection with the Rift Valley fever virus (RVFV) has the capacity to cause fatal hemorrhagic fever in humans. A unique characteristic of RVFV infection is the presence of nuclear filaments whose formation is linked to synthesis of the viral NSs protein. We identify a crucial interaction between a ΩX a V motif present in the NSs protein and the p62 subunit of the host TFIIH. This interaction is required for nuclear filament formation, NSs-dependent degradation of p62 and for virulence. This ΩX a V motif is also found in human proteins that bind p62 and our results are an example of how viruses incorporate simple motifs into their protein sequences to mimic human proteins and enhance their functional capabilities in host cells during infections. Rift Valley fever virus (RVFV) is a single-stranded RNA virus capable of inducing fatal hemorrhagic fever in humans. A key component of RVFV virulence is its ability to form nuclear filaments through interactions between the viral nonstructural protein NSs and the host general transcription factor TFIIH. Here, we identify an interaction between a ΩX a V motif in NSs and the p62 subunit of TFIIH. This motif in NSs is similar to ΩX a V motifs found in nucleotide excision repair (NER) factors and transcription factors known to interact with p62. Structural and biophysical studies demonstrate that NSs binds to p62 in a similar manner as these other factors. Functional studies in RVFV-infected cells show that the ΩX a V motif is required for both nuclear filament formation and degradation of p62. Consistent with the fact that the RVFV can be distinguished from other Bunyaviridae -family viruses due to its ability to form nuclear filaments in infected cells, the motif is absent in the NSs proteins of other Bunyaviridae -family viruses. Taken together, our studies demonstrate that p62 binding to NSs through the ΩX a V motif is essential for degrading p62, forming nuclear filaments and enhancing RVFV virulence. In addition, these results show how the RVFV incorporates a simple motif into the NSs protein that enables it to functionally mimic host cell proteins that bind the p62 subunit of TFIIH.