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

SARS coronavirus (CoV) papain-like protease (PLpro) reportedly induced the production of TGF-beta 1 through p38 MAPK/STAT3-meidated Egr-l-dependent activation (Sci. Rep. 6, 25754). This study investigated the correlation of PLpro-induced TGF-beta 1 with the expression of Type I collagen in human lung epithelial cells and mouse pulmonary tissues. Specific inhibitors for TGF-beta RI, p38 MAPK, MEK, and STAT3 proved that SARS-CoV PLpro induced TGF-beta 1-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-beta 1 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-beta RI and STAT6 (AS1517499) ascertained that STAT6 activation was required for PLpro-induced TGF-beta 1-dependent up-regulation of Type I collagen in human lung epithelial cells. The results showed that SARS-CoV PLpro stimulated TGF-beta 1-dependent expression of Type I collagen via activating STAT6 pathway.