Measles virus suppresses interferon-α signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins, C and V, with interferon-α receptor complex

Abstract

To establish infections, viruses use various strategies to suppress the host defense mechanism, such as interferon (IFN)-induced antiviral state. We found that cells infected with a wild strain of measles virus (MeV) displayed nearly complete suppression of IFN-alpha-induced antiviral state, but not IFN-gamma-induced state. This phenomenon is due to the suppression of IFN-alpha-inducible gene expression at a transcriptional level. In the IFN-alpha signal transduction pathway, Jak1 phosphorylation induced by IFN-alpha is dramatically suppressed in MeV-infected cells; however, phosphorylation induced by IFN-gamma is not. We performed immunoprecipitation experiments using antibodies against type 1 IFN receptor chain 1 (INFAR1) and antibody against RACK1, which is reported to be a scaffold protein interacting with type I IFN receptor chain 2 and STAT1. These experiments indicated that IFNAR1 forms a complex containing the MeV-accessory proteins C and V, RACK1, and STAT1 in MeV-infected cells but not in uninfected cells. Composition of this complex in the infected cells altered little by IFN-alpha treatment. These results indicate that MeV suppresses the IFN-alpha, but not IFN-gamma, signaling pathway by inhibition of Jak1 phosphorylation. Our data suggest that functional disorder of the type I IFN receptor complex is due to "freezing" of the receptor through its association with the C and/or V proteins of MeV.

High CD46 Receptor Density Determines Preferential Killing of Tumor Cells by Oncolytic Measles Virus

“…If these antiviral mechanisms are induced by MV-Edm infection, they will serve to amplify the difference in selectivity conferred by the role of CD46 density in regulating CPEs. However, MV-Edm encodes V and C viral proteins that can respond to the host defense by antagonizing IFN-␣/␤ production and signaling (11)(12)(13)(14)(15). We also determined that viral protein synthesis in infected normal cells was only 2-4-fold lower compared with infected tumor cells, and the striking difference in CPEs cannot therefore be explained by a preferential shutdown of viral protein synthesis in these normal cells as part of their antiviral response.…”

“…However, viruses have evolved diverse strategies to evade or antagonize the IFN antiviral response (11). Thus, measles virus (MV) encodes the V and C accessory proteins that block IFN-␣/␤ production and/or signaling, allowing the virus to replicate in the host cell (12)(13)(14)(15). The mechanism underlying MV-C inhibition of IFN-␣/␤ signaling remains unclear (15), but the MV-V protein blocks the IFN response by inhibiting phosphorylation of signal transducers and activators of transcription 1 and 2 proteins (13).…”

Suppression of Thermotolerance in Mumps Virus-infected Cells Is Caused by Lack of HSP27 Induction Contributed by STAT-1

“…The most effective route to global suppression would be to shut off the IFN signal transduction pathway through adjacent IFN receptors, such as the JAK/STAT pathway, rather than to inhibit effector molecules such as 2Ј,5Ј-oligoadenylate synthetase and double-stranded RNA-dependent protein kinase, which are induced by IFN. For example, the measles virus suppresses IFN-␣-induced Jak1 phosphorylation but not IFN-␥-induced Tyr phosphorylation (18), which seems to have a mild effect on host cells. In contrast, the accelerated degradation of STAT1 proteins by the mumps virus seems to have a very severe effect to host cells, causing almost complete suppression of both IFN-␣ and IFN-␥ signal transduction.…”

“…Immunoprecipitation Analysis-Immunoprecipitation was carried out as described previously (18,45). Briefly, cells were lysed in radioimmune precipitation buffer (1% Nonidet P-40, 100 mM NaCl, 4 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 5 g/ml aprotinin, 1 mM Na 3 VO 4 , 1 mM NaF, and 50 mM HEPES-NaOH, pH 7.5).…”

“…Viruses belonging to the genus Respirovirus within the family Paramyxoviridae, such as Sendai virus and human parainfluenza virus type 3, reduce the Tyr phosphorylation of STAT-1 (14 -17). More recently, we showed that the measles virus, a Morbillivirus, inhibits the Tyr phosphorylation of Jak1 induced by IFN-␣, but not that induced by IFN-␥ (18). Viruses belonging to the genus Rubulavirus have been shown to dramatically reduce the basal level of STAT proteins.…”