SARS coronavirus papain-like protease up-regulates the collagen expression through non-Samd TGF-β1 signaling

Virus Res. 2017 May 2:235:58-66. doi: 10.1016/j.virusres.2017.04.008. Epub 2017 Apr 13.

Abstract

SARS coronavirus (CoV) papain-like protease (PLpro) reportedly induced the production of TGF-β1 through p38 MAPK/STAT3-meidated Egr-1-dependent activation (Sci. Rep. 6, 25754). This study investigated the correlation of PLpro-induced TGF-β1 with the expression of Type I collagen in human lung epithelial cells and mouse pulmonary tissues. Specific inhibitors for TGF-βRI, p38 MAPK, MEK, and STAT3 proved that SARS-CoV PLpro induced TGF-β1-dependent up-regulation of Type I collagen in vitro and in vivo. Subcellular localization analysis of SMAD3 and SMAD7 indicated that non-SMAD pathways in TGF-β1 signaling involved in the production of Type I collagen in transfected cells with pSARS-PLpro. Comprehensive analysis of ubiquitin-conjugated proteins using immunoprecipitation and nanoLC-MS/MS indicated that SARS-CoV PLpro caused the change in the ubiquitination profile of Rho GTPase family proteins, in which linked with the increase of Rho-like GTPase family proteins. Moreover, selective inhibitors TGF-βRI and STAT6 (AS1517499) ascertained that STAT6 activation was required for PLpro-induced TGF-β1-dependent up-regulation of Type I collagen in human lung epithelial cells. The results showed that SARS-CoV PLpro stimulated TGF-β1-dependent expression of Type I collagen via activating STAT6 pathway.

Keywords: Collagen; Papain-like protease; SARS-CoV; STAT6; TGF-β1.

MeSH terms

  • Animals
  • Cells, Cultured
  • Collagen / biosynthesis*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / metabolism*
  • Epithelial Cells / pathology
  • Epithelial Cells / virology
  • Gene Expression
  • Host-Pathogen Interactions*
  • Humans
  • Mice
  • STAT6 Transcription Factor / metabolism*
  • Severe acute respiratory syndrome-related coronavirus / physiology*
  • Signal Transduction*
  • Transforming Growth Factor beta1 / metabolism*
  • Up-Regulation
  • Viral Proteins / metabolism*

Substances

  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Transforming Growth Factor beta1
  • Viral Proteins
  • Collagen
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases