The Rabies Virus Interferon Antagonist P Protein Interacts with Activated STAT3 and Inhibits Gp130 Receptor Signaling

Abstract

Immune evasion by rabies virus depends on targeting of the signal transducers and activator of transcription 1 (STAT1) and STAT2 proteins by the viral interferon antagonist P protein, but targeting of other STAT proteins has not been investigated. Here, we find that P protein associates with activated STAT3 and inhibits STAT3 nuclear accumulation and Gp130-dependent signaling. This is the first report of STAT3 targeting by the interferon antagonist of a virus other than a paramyxovirus, indicating that STAT3 antagonism is important to a range of human-pathogenic viruses.

Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

“…The mumps viral V protein can target STAT3 to ubiquitin-mediated degradation45 and the V protein of measles forms a complex with STAT proteins to prevent nuclear translocation46. The P protein of rabies virus associates with STAT3 in an oncostatin M- dependent manner to inhibit STAT3 activation47. STAT3 is also inhibited by the human cytomegalovirus (hCMV)48 and the human metapneumovirus (hMPV)49.…”

Identification of a Role for Nucleolin in Rabies Virus Infection

“…The RABV phosphoprotein (P-protein) has critical roles in genome transcription/replication and antagonism of interferon (IFN)-dependent antiviral responses (2)(3)(4)(5)(6)(7)(8)(9). In infected cells, the P gene produces full-length P-protein (P1) and several N-terminally truncated isoforms, predominantly P2 and P3, via a ribosomal leaky scanning mechanism (7,10).…”

Recombinant rabies virus expressing IFNα1 enhanced immune responses resulting in its attenuation and stronger immunogenicity

“…responses in the host (Randall and Goodbourn, 2008). In previous studies, RABV phosphoprotein P was confirmed to be an IFN antagonist that plays a major and multifunctional role in disturbing interferon gene expression, interferon-induced STAT signaling, and the functions of antiviral protein (Lieu et al, 2013;Vidy et al, 2007;Wiltzer et al, 2014). Although RABVs have developed advanced countermeasures against the IFN system, the interferon-mediated mechanisms are still the main factors restricting RABV replication in vivo (Carty et al, 2014;Faul et al, 2009;Schoggins et al, 2011).…”