Promotion of Myoblast Differentiation by Fkbp5 via Cdk4 Isomerization

Mercedes Ruiz-Estevez, James Staats, Ellen Paatela, Dane Munson, Nobuko Katoku-Kikyo, Ce Yuan, Yoko Asakura, Reilly Hostager, Hiroshi Kobayashi, Atsushi Asakura, Nobuaki Kikyo

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Fkbp5 is a widely expressed peptidyl prolyl isomerase that serves as a molecular chaperone through conformational changes of binding partners. Although it regulates diverse protein functions, little is known about its roles in myogenesis. We found here that Fkbp5 plays critical roles in myoblast differentiation through two mechanisms. First, it sequesters Cdk4 within the Hsp90 storage complex and prevents the formation of the cyclin D1-Cdk4 complex, which is a major inhibitor of differentiation. Second, Fkbp5 promotes cis-trans isomerization of the Thr172-Pro173 peptide bond in Cdk4 and inhibits phosphorylation of Thr172, an essential step for Cdk4 activation. Consistent with these in vitro findings, muscle regeneration is delayed in Fkbp5−/− mice. The related protein Fkbp4 also sequesters Cdk4 within the Hsp90 complex but does not isomerize Cdk4 or induce Thr173 phosphorylation despite its highly similar sequence. This study demonstrates protein isomerization as a critical regulatory mechanism of myogenesis by targeting Cdk4. Ruiz-Estevez et al. show that Fkbp5 inhibits Cdk4 activity by sequestering it in the Hsp90 complex and preventing phosphorylation at T172 through isomerization of P173. Lack of Cdk4 activity inhibits proliferation and promotes myogenesis. This study provides evidence that Fkbp5 functions as an isomerase necessary for myogenesis.

Original languageEnglish (US)
Pages (from-to)2537-2551.e8
JournalCell reports
Volume25
Issue number9
DOIs
StatePublished - Nov 27 2018

Bibliographical note

Funding Information:
We thank Matthew Lowe and Michaela Lohman for technical support and Toshio Kitamura for the plasmid pMXs-IP and PLAT-E cells. We acknowledge the Minnesota Supercomputing Institute, University of Minnesota Informatics Institute, and University of Minnesota Genomics Center for RNA-seq, high performance computing resources, and the gopher pipelines. We thank the University Flow Cytometry Resource supported by the NIH ( 5P30CA077598-20 ). We recognize the Center for Mass Spectrometry and Proteomics at the University of Minnesota and various supporting agencies, including the National Science Foundation for Major Research Instrumentation grants 9871237 and NSF-DBI-0215759 used to purchase the instruments described in this study. Supporting agencies are listed at the following: http://cbs.umn.edu/msp/about . C.Y. was supported by the Minnesota Stem Cell Institute and the University of Minnesota Informatics Institute Graduate Fellowship (MnDrive). A.A. was supported by the NIH ( R01 AR062142 and R21 AR070319 ). N.K. was supported by the NIH ( R01 GM098294 , R21 AR066158 , R21 HD083648 , and R21 CA187232 ) and Engdahl Family Foundation . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Funding Information:
We thank Matthew Lowe and Michaela Lohman for technical support and Toshio Kitamura for the plasmid pMXs-IP and PLAT-E cells. We acknowledge the Minnesota Supercomputing Institute, University of Minnesota Informatics Institute, and University of Minnesota Genomics Center for RNA-seq, high performance computing resources, and the gopher pipelines. We thank the University Flow Cytometry Resource supported by the NIH (5P30CA077598-20). We recognize the Center for Mass Spectrometry and Proteomics at the University of Minnesota and various supporting agencies, including the National Science Foundation for Major Research Instrumentation grants 9871237 and NSF-DBI-0215759 used to purchase the instruments described in this study. Supporting agencies are listed at the following: http://cbs.umn.edu/msp/about. C.Y. was supported by the Minnesota Stem Cell Institute and the University of Minnesota Informatics Institute Graduate Fellowship (MnDrive). A.A. was supported by the NIH (R01 AR062142 and R21 AR070319). N.K. was supported by the NIH (R01 GM098294, R21 AR066158, R21 HD083648, and R21 CA187232) and Engdahl Family Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© 2018 The Authors

Keywords

  • Cdk4
  • Fkbp4
  • Fkbp5
  • cell cycle
  • cell proliferation
  • muscle differentiation
  • muscle regeneration
  • myoblast
  • peptidyl prolyl isomerase

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