Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion

Noumeira Hamoud, Viviane Tran, Takahiro Aimi, Wataru Kakegawa, Sylvie Lahaie, Marie Pier Thibault, Ariane Pelletier, G. William Wong, In San Kim, Artur Kania, Michisuke Yuzaki, Michel Bouvier, Jean François Côté

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Myoblast fusion is tightly regulated during development and regeneration of muscle fibers. BAI3 is a receptor that orchestrates myoblast fusion via Elmo/Dock1 signaling, but the mechanisms regulating its activity remain elusive. Here we report that mice lacking BAI3 display small muscle fibers and inefficient muscle regeneration after cardiotoxin-induced injury. We describe two proteins that repress or activate BAI3 in muscle progenitors. We find that the secreted C1q-like1–4 proteins repress fusion by specifically interacting with BAI3. Using a proteomic approach, we identify Stabilin-2 as a protein that interacts with BAI3 and stimulates its fusion promoting activity. We demonstrate that Stabilin-2 activates the GPCR activity of BAI3. The resulting activated heterotrimeric G-proteins contribute to the initial recruitment of Elmo proteins to the membrane, which are then stabilized on BAI3 through a direct interaction. Collectively, our results demonstrate that the activity of BAI3 is spatiotemporally regulated by C1qL4 and Stabilin-2 during myoblast fusion.

Original languageEnglish
Article number4470
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

Bibliographical note

Funding Information:
We thank Dr. D.R. Hipfner (IRCM) for critical reading of the manuscript. We recognize the technical support of Meirong Liang (IRCM) and expertise of the IRCM Microscopy (Dr. D. Filion) and Mass Spectrometry (Dr. D. Faubert) platforms. We thank Dr. Arhamatoulaye Maiga (IRIC) for guidance in BRET2 experiments. We acknowledge Dr. E.N. Harris (University of Nebraska) for the generous gift of Stabilin-2 plasmid. We acknowledge Dr. T.C. Südhof (Stanford University) for support and sharing reagents. This work was funded by an NIH grant (DK084171) to G.W.W and CIHR grants to J.-F. C. (PJT-153065), M.B. (FDN-148431) and A.K. (MOP-77556 and MOP-97758). N.H. and V.T. are recipients of Ph.D. studentships from the Fonds de Recherche du Québec-Santé (FRQ-S). M.B. holds a Canada Research Chairs in Signal Transduction and Molecular Pharmacology. J.-F.C. is a recipient of a Senior Investigator Award from the FRQ-S and holds the TRANSAT chair in Breast Cancer Research.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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