title: mTORC1 phosphorylates LARP6 to stimulate type I collagen expression.
abstract: Excessive deposition of type I collagen causes fibrotic diseases. Binding of La ribonucleoprotein domain family, member 6 (LARP6) to collagen mRNAs regulates their translation and is necessary for high type I collagen expression. Here we show that mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A mutant of LARP6 acts as a dominant negative protein in collagen biosynthesis, which retards secretion of type I collagen and causes excessive posttranslational modifications. Similar effects are seen using mTORC1 inhibitor rapamycin or by knocking down raptor. The S348A/S409A mutant weakly interacts with the accessory protein STRAP, needed for coordinated translation of collagen mRNAs. The interaction of wt LARP6 and STRAP is also attenuated by rapamycin and by raptor knockdown. Additionally, in the absence of S348/S409 phosphorylation LARP6 is sequestered in increasing amounts at the ER membrane. We postulate that phosphorylation of S348/S409 by mTORC1 stimulates the interaction of LARP6 and STRAP to coordinate translation of collagen mRNAs and to release LARP6 from the ER for new round of translation. These mechanisms contribute to high level of collagen expression in fibrosis.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Branko
authors.initials: B
authors.lastname: Stefanovic
mesh_terms: D001324:Autoantigens / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D000097585:SS-B Antigen
chemical_list: D001324:Autoantigens; D024042:Collagen Type I; D000076222:Mechanistic Target of Rapamycin Complex 1; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D020123:Sirolimus; D000097585:SS-B Antigen; C403447:STRAP protein, human