STAT3 Ubiquitylation and Degradation by Mumps Virus Suppress Cytokine and Oncogene Signaling

Abstract

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.Gene expression and biological responses to cytokines and polypeptide growth factors are often mediated by signal transducer and activator of transcription (STAT) proteins (12). The activities of various STAT proteins control cell growth and differentiation, organogenesis, embryonic development, and host responses to cancer and infection. Inappropriate activation of STAT signaling is frequently observed in human diseases, including inflammation, asthma, autoimmunity, and cancer, suggesting that inhibitors of STAT factors might be of wide-ranging therapeutic value (reviewed in reference 55 and references therein).Of the seven mammalian STAT proteins, STAT1, STAT2, and STAT3 exhibit the broadest expression profiles and respond to activating stimuli in most cell types (70, 71). A transcription factor complex, ISGF3, containing activated STAT1 and STAT2 is essential for induction of alpha/beta interferon (IFN-␣/␤) target genes that establish an innate cellular antiviral state (54). Similarly, the transcriptional response to IFN-␥ is mediated by a STAT1 homodimer that is required for IFN-␥-dependent innate and adaptive immune responses (31). The third widely expressed STAT protein, STAT3, is activated by many cytokine systems, including interleukin 6 (IL-6), leukemia inhibitory factor, ciliary neurotrophic factor, oncostatin M, and leptin (reviewed in reference 28). STAT3 is also activated by growth factor receptors with intrinsic protein tyrosine kinase activity (e.g., platelet-derived and epidermal growth factor receptors [53,61]) as well as cellular and viral cytoplasmic tyrosine kinases (e.g., c-Src and v-Src [6,68]).Targeted disruption of STAT3 in mice results in early embryonic lethality (57). Tissue-specific disruption has revealed diverse STAT3 functions in mammary gland, liver, keratinocytes, thymus, blood, and neurons that are involved in growth and differentiation, inflammation, liver regeneration, acutephase responses...

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

“…This codependent relationship between STAT1 and STAT2 is somewhat similar to the requirement for accessory STAT proteins in IFN signaling evasion by the Rubulavirus V protein-dependent ubiquitin ligases. Both SV5 and mumps virus V proteins strictly require cellular STAT2 expression to target STAT1, whereas human parainfluenza virus 2 requires cellular STAT1 for STAT2 targeting (19,29). In fact, for SV5, the requirement for STAT2 provides the molecular basis for host range restriction, as the murine STAT2 orthologue fails to support STAT1 degradation and IFN evasion (20).…”

“…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.…”

“…Current evidence from the study of several family members indicates that the common outcome of STAT targeting and IFN evasion is achieved by individual paramyxovirus species through a diverse range of molecular mechanisms. 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).…”

The G1 phase E3 ubiquitin ligase TRUSS that gets deregulated in human cancers is a novel substrate of the S-phase E3 ubiquitin ligase Skp2

“…Viruses belonging to paramyxovirus family such as simian virus 5, human parainfluenza virus type 2 and mumps virus use DDB1-Cul4 to degrade signal transducer and activator of transcription protein which otherwise would mount an antiviral interferon response. [15][16][17] The HBx protein of Hepatitis B virus (HBV) is also known to bind DDB1 possibly to facilitate viral replication by extending the S phase of cell cycle. 18,19 Further, HBx is shown to stabilize c-Myc by disrupting the SCF Skp2 complex and interfering with its ubiquitination.…”

Mumps virus pathogenesis: Insights and knowledge gaps

“…In this way, IFN and IL-6 signaling are blocked and the virus can evade both innate and adaptive antiviral responses. [18][19][20][21][22] Furthermore, blockage of the IFN pathway enhances mumps virus replication, as IFN inhibitors promote mumps virus replication in vitro. 23 However, the effect of the V protein on the magnitude of the IFN and IL-6 response is unclear, because IFN and IL-6 levels appear to be elevated in mumps patients, especially in patients with meningitis and/or encephalitis.…”