Henipavirus V protein association with Polo-like kinase reveals functional overlap with STAT1 binding and interferon evasion.
Emerging viruses in the paramyxovirus genus Henipavirus evade host antiviral responses via protein interactions between the viral V and W proteins and cellular STAT1 and STAT2 and the cytosolic RNA sensor MDA5. Polo-like kinase (PLK1) is identified as being an additional cellular partner that can bind to Nipah virus P, V, and W proteins. For both Nipah virus and Hendra virus, contact between the V protein and the PLK1 polo box domain is required for V protein phosphorylation. Results indicate that PLK1 is engaged by Nipah virus V protein amino acids 100 to 160, previously identified as being the STAT1 binding domain responsible for host interferon (IFN) signaling evasion, via a Thr-Ser-Ser-Pro motif surrounding residue 130. A distinct Ser-Thr-Pro motif surrounding residue 199 mediates the PLK1 interaction with Hendra virus V protein. Select mutations in the motif surrounding residue 130 also influenced STAT1 binding and innate immune interference, and data indicate that the V:PLK1 and V:STAT complexes are V mediated yet independent of one another. The effects of STAT1/PLK1 binding motif mutations on the function the Nipah virus P protein in directing RNA synthesis were tested. Remarkably, mutations that selectively disrupt the STAT or PLK1 interaction site have no effects on Nipah virus P protein-mediated viral RNA synthesis. Therefore, mutations targeting V protein-mediated IFN evasion will not alter the RNA synthetic capacity of the virus, supporting an attenuation strategy based on disrupting host protein interactions.
Ludlow
Louise E
LE
Department of Medicine, Northwestern University, Evanston, Illinois 60208-3500, USA.
Lo
Michael K
MK
Rodriguez
Jason J
JJ
Rota
Paul A
PA
Horvath
Curt M
CM
D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D045403:Henipavirus / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000276:immunology*; D008156:Luciferases; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D007370:Interferon Type I; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015678:Viral Structural Proteins; D000097869:Polo-Like Kinase 1; C494079:STAT1 protein, human