STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling.
Mumps virus is a common infectious agent of humans, causing parotitis, meningitis, encephalitis, and orchitis. Like other paramyxoviruses in the genus Rubulavirus, mumps virus catalyzes the proteasomal degradation of cellular STAT1 protein, a means for escaping antiviral responses initiated by alpha/beta and gamma interferons. We demonstrate that mumps virus also eliminates cellular STAT3, a protein that mediates transcriptional responses to cytokines, growth factors, nonreceptor tyrosine kinases, and a variety of oncogenic stimuli. STAT1 and STAT3 are independently targeted by a single mumps virus protein, called V, that assembles STAT-directed ubiquitylation complexes from cellular components, including STAT1, STAT2, STAT3, DDB1, and Cullin4A. Consequently, mumps virus V protein prevents responses to interleukin-6 and v-Src signals and can induce apoptosis in STAT3-dependent multiple myeloma cells and transformed murine fibroblasts. These findings demonstrate a unique cytokine and oncogene evasion property of mumps virus that provides a molecular basis for its observed oncolytic properties.
Ulane
Christina M
CM
Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
Rodriguez
Jason J
JJ
Parisien
Jean-Patrick
JP
Horvath
Curt M
CM
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016391:Genes, src / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009109:Mumps virus / Q000472:pathogenicity* / Q000502:physiology; D009857:Oncogenes / Q000502:physiology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D025801:Ubiquitin; D014764:Viral Proteins; D016899:Interferon-beta