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mTORC1 phosphorylates LARP6 to stimulate type I collagen expression
Yujie Zhang1, Branko Stefanovic1
1Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
Scientific Reports
|January 24, 2017
Summary
La ribonucleoprotein domain family, member 6 (LARP6) phosphorylation by mTORC1 is crucial for collagen production. This process regulates LARP6 interaction with STRAP, impacting collagen biosynthesis and fibrotic disease development.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Fibrotic diseases are characterized by excessive type I collagen deposition.
- La ribonucleoprotein domain family, member 6 (LARP6) binds collagen mRNAs, regulating their translation and type I collagen expression.
Purpose of the Study:
- To investigate the role of mTORC1 in regulating LARP6 activity and collagen biosynthesis.
- To elucidate the molecular mechanisms by which LARP6 controls collagen production.
Main Methods:
- Site-directed mutagenesis to create LARP6 phosphorylation mutants (S348A/S409A).
- Western blotting and immunoprecipitation to assess protein interactions and phosphorylation.
- Collagen secretion assays and analysis of posttranslational modifications.
- Rapamycin treatment and raptor knockdown to inhibit mTORC1 signaling.
Main Results:
- mTORC1 phosphorylates LARP6 at S348 and S409.
- A non-phosphorylatable LARP6 mutant (S348A/S409A) impaired collagen secretion and increased posttranslational modifications.
- mTORC1 inhibition (rapamycin or raptor knockdown) mimicked the effects of the LARP6 mutant.
- Phosphorylation of LARP6 by mTORC1 enhances its interaction with STRAP, facilitating collagen mRNA translation and preventing ER sequestration.
Conclusions:
- mTORC1-mediated phosphorylation of LARP6 is a key regulatory step in collagen biosynthesis.
- This phosphorylation event is essential for the coordinated translation of collagen mRNAs and proper LARP6 function.
- Dysregulation of this pathway contributes to the high collagen expression observed in fibrotic diseases.
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