STAT Protein Interference and Suppression of Cytokine Signal Transduction by Measles Virus V Protein

Abstract

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 virusinfected 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.Cytokine signal transduction is essential for normal immune function and controls the quality of responses to a wide variety of microbial infections. Innate and adaptive host responses to virus infections are regulated by autocrine and paracrine cytokine signaling systems. For most cytokines, receptor binding triggers an intracellular signaling cascade involving one or more signal transducer and activator of transcription (STAT) proteins. Diverse cytokine and growth factor signaling pathways produce active STAT transcription factors that specify mRNA induction profiles (26). For example, the alpha and beta interferon (IFN-␣/␤) family is of primary importance for both innate and adaptive antiviral immunity (reviewed in references 1, 49, and 53). In the innate antiviral system, IFN-␣/␤ initiates a receptor-mediated signaling system that produces an activated STAT1-STAT2-IRF9 heterotrimeric transcription complex known as ISGF3 (27). The ISGF3 complex translocates to the nucleus, where it can bind to target gene promoter elements and induce the transcription of host antiviral genes. Similarly, IFN-␥, a cytokine that mediates both innate and adaptive immune responses critical for defense against microbial infections and cancer (21), activates a homodimeric STAT1 transcription factor, GAF (9). Interleukin 6 (IL-6), a cytokine required for acute-phase responses, liver regeneration, B-cell maturation, and macrophage differentiation, activates STAT3 homodimers, a response in common with growth factor pathways (69) and onco...

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).…”

Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

“…It is also likely that Henipavirus V proteins have evolved to use different peptide regions to counteract IFN signaling, while the conservation of the CTD is reflective of a broader function in the context of virus infection. It may be relevant that other paramyxoviruses have been demonstrated to form intracytoplasmic inclusions that contain viral proteins, nucleic acids, IRF3, and STATs (6,17,29), but more detailed analysis of V protein functions in the context of intact viruses will be required to shed light on the precise role of the CTD.…”

“…For example, the Rubulaviruses, simian virus 5 (SV5), human parainfluenza virus 2, and mumps virus all encode STAT-directed E3 ubiquitin ligase activities that function in combination with cellular proteins to target STAT1, STAT2, or STAT3 for proteasomal degradation (5,18,19,28,29). Distinctly, measles virus, a prototype Morbillivirus, does not induce STAT ubiquitylation and degradation but instead prevents IFN-induced ISGF3 assembly and STAT protein nuclear translocation (17,27). These IFN evasion mechanisms rely on protein-protein interactions between STATs and the paramyxovirus-encoded V protein.…”

Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond

“…Cyt & Nuc (Palosaari et al, 2003;Ramachandran et al, 2008) Cyt & Nuc (Wardrop & Briedis, 1991) N & P?# (Liston et al, 1995;Tober et al, 1998) MDA5 (Cyt) ;…”