A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses
type: CreativeWork
description: Vaccinia virus (VACV) is a member of the poxviridae, a family of viruses with large double-stranded, linear DNA genomes that replicate in the cytoplasm of cells. The genome of vaccinia encodes over 200 proteins, many of which have been shown to function as inhibitors of the innate immune response. This includes at least four proteins that directly target interferon (IFN)-induced signalling. Here we report the first function of the uncharacterised, 60 aa 018 protein from VACV strain western reserve. The 018 protein was expressed early during infection and found to potently inhibit type I and type II IFN-induced signalling. Cellular protein STAT1, a crucial protein required for IFN-induced signal transduction, was identified as a direct binding partner of 018. Mapping experiment identified the SH2 domain of STAT1, a region important for STAT1 recruitment to IFN-receptors, as the site of 018 binding. In cells expressing 018, STAT1 failed to be phosphorylated, thereby preventing STAT1 activation. Taking the type II IFN pathway as a model, we demonstrated mechanistically, 018 was able to outcompete the binding of STAT1 to the activated IFN receptor. To gain further mechanistic insight, the co-crystal structure of the 018:STAT1 complexed was determined. This showed 018 forms a -hairpin fold whereby the two strands of the peptide augment the central -sheet of the SH2 domain. Unlike canonical SH2 ligand interactions, 018 did not bind into the pTyr pocket and thus presents a novel pTyr pocket binding independent mode of binding at an SH2 domain. To further study the role of 018 during infection, recombinant viruses lacking 018 were constructed and tested in an in vivo mouse model. Deletion 018 viruses were found to be attenuated despite the presence of addition viral IFN-induced signalling inhibitors, confirming the biological importance of 018 during infection. Comparison of the IFN antagonist V protein from Nipah virus, a member of the paramyxovirus family showed sequen…
abstract: Vaccinia virus (VACV) is a member of the poxviridae, a family of viruses with large double-stranded, linear DNA genomes that replicate in the cytoplasm of cells. The genome of vaccinia encodes over 200 proteins, many of which have been shown to function as inhibitors of the innate immune response. This includes at least four proteins that directly target interferon (IFN)-induced signalling. Here we report the first function of the uncharacterised, 60 aa 018 protein from VACV strain western reserve. The 018 protein was expressed early during infection and found to potently inhibit type I and type II IFN-induced signalling. Cellular protein STAT1, a crucial protein required for IFN-induced signal transduction, was identified as a direct binding partner of 018. Mapping experiment identified the SH2 domain of STAT1, a region important for STAT1 recruitment to IFN-receptors, as the site of 018 binding. In cells expressing 018, STAT1 failed to be phosphorylated, thereby preventing STAT1 activation. Taking the type II IFN pathway as a model, we demonstrated mechanistically, 018 was able to outcompete the binding of STAT1 to the activated IFN receptor. To gain further mechanistic insight, the co-crystal structure of the 018:STAT1 complexed was determined. This showed 018 forms a -hairpin fold whereby the two strands of the peptide augment the central -sheet of the SH2 domain. Unlike canonical SH2 ligand interactions, 018 did not bind into the pTyr pocket and thus presents a novel pTyr pocket binding independent mode of binding at an SH2 domain. To further study the role of 018 during infection, recombinant viruses lacking 018 were constructed and tested in an in vivo mouse model. Deletion 018 viruses were found to be attenuated despite the presence of addition viral IFN-induced signalling inhibitors, confirming the biological importance of 018 during infection. Comparison of the IFN antagonist V protein from Nipah virus, a member of the paramyxovirus family showed sequen…
author: Talbot-Cooper, Callum
language: eng
keywords: Poxviruses, Vaccinia, Innate immunity, IFN-signalling, STAT1, Paramyoxviruses, Nipah virus
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-01-27
date modified: 2026-07-22T22:24:14Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.86923