A ΩXaV motif in the Rift Valley fever virus NSs protein is essential for degrading p62, forming nuclear filaments and virulence.
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 ΩXaV motif in NSs and the p62 subunit of TFIIH. This motif in NSs is similar to ΩXaV 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 ΩXaV 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 ΩXaV 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.
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada H3C 3J7; and.
Normand
N
Cyr
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110.
Cynthia
C
de la Fuente
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada H3C 3J7; and.
Lauriane
L
Lecoq
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110.
Irene
I
Guendel
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada H3C 3J7; and.
Philippe R
PR
Chabot
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110 jg.omichinski@umontreal.ca kkehnhal@gmu.edu.
Kylene
K
Kehn-Hall
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada H3C 3J7; and jg.omichinski@umontreal.ca kkehnhal@gmu.edu.
James G
JG
Omichinski
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004847:Epithelial Cells / Q000821:virology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012296:Rift Valley fever virus; D017386:Sequence Homology, Amino Acid; D051758:Transcription Factor TFIIH / Q000378:metabolism*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics; D014774:Virulence
D017361:Viral Nonstructural Proteins; D051758:Transcription Factor TFIIH; D046988:Proteasome Endopeptidase Complex
NMR spectroscopy; NSs; Rift Valley Fever Virus; TFIIH; nuclear filaments