A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses

Abstract

The induction of interferon-stimulated genes by signal transducer and activator of transcription (STAT) proteins, is a critical host defence to fight virus infections. Here, a highly expressed poxvirus protein 018 is shown to inhibit IFN-induced signalling by binding the SH2 domain of STAT1 to prevent STAT1 association with an activated IFN receptor. Despite the presence of additional inhibitors of IFN-induced signalling, a poxvirus lacking 018 was attenuated in mice. The 2.0-angstrom crystal structure of the 018:STAT1 complex reveals a mechanism for a high-affinity, pTyr-independent mode of binding to an SH2 domain. Furthermore, the STAT1 binding motif of 018 shows sequence similarity to the STAT1-binding proteins from Nipah virus, which like 018, block the association of STAT1 with an IFN receptor. Taken together, these results provide detailed mechanistic insight into a potent mode of STAT1 antagonism, found to exist in genetically diverse virus families.

Selective modulation of cell surface proteins during vaccinia infection: A resource for identifying viral immune evasion strategies

“…VACV is well-known to interfere with cytokine signalling by expressing soluble binding proteins, or decoy receptors, for IL-1β, TNFα, IL-18, IFN-γ and IFN-α/β [11]. In addition, IFN signalling is targeted at several levels in the pathway downstream of the receptor [76,77]. The observed downregulation of IFNAR2 (type I IFN receptor) and IL10-RB (a component of multiple cytokine receptors, including type III IFNs) from the PM, may represent novel VACV strategies for evasion of the IFN response.…”