STAT protein interference and suppression of cytokine signal transduction by measles virus V protein.
Measles virus, a paramyxovirus of the Morbillivirus genus, is responsible for an acute childhood illness that infects over 40 million people and leads to the deaths of more than 1 million people annually (C. J. Murray and A. D. Lopez, Lancet 349:1269-1276, 1997). Measles virus infection is characterized by virus-induced immune suppression that creates susceptibility to opportunistic infections. Here we demonstrate that measles virus can inhibit cytokine responses by direct interference with host STAT protein-dependent signaling systems. Expression of the measles V protein prevents alpha, beta, and gamma interferon-induced transcriptional responses. Furthermore, it can interfere with signaling by interleukin-6 and the non-receptor tyrosine kinase, v-Src. Affinity purification demonstrates that the measles V protein associates with cellular STAT1, STAT2, STAT3, and IRF9, as well as several unidentified partners. Mechanistic studies indicate that while the measles V protein does not interfere with STAT1 or STAT2 tyrosine phosphorylation, it causes a defect in IFN-induced STAT nuclear accumulation. The defective STAT nuclear redistribution is also observed in measles virus-infected cells, where some of the STAT protein is detected in cytoplasmic bodies that contain viral nucleocapsid protein and nucleic acids. Interference with STAT-inducible transcription may provide a novel intracellular mechanism for measles virus-induced cytokine inhibition that links innate immune evasion to adaptive immune suppression.
Palosaari
Heidi
H
Immunobiology Center, Mount Sinai School of Medicine, One Gustave L. Levy Pl., Box 1630, New York, NY 10029, USA.
Parisien
Jean-Patrick
JP
Rodriguez
Jason J
JJ
Ulane
Christina M
CM
Horvath
Curt M
CM
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*
D016207:Cytokines; D010750:Phosphoproteins; D015534:Trans-Activators; C069181:V protein, measles virus; D014764:Viral Proteins