Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex

  1. Meng Shi
  2. Hieng Chiong Tie
  3. Mahajan Divyanshu
  4. Xiuping Sun
  5. Yan Zhou
  6. Boon Kim Boh
  7. Leah A Vardy
  8. Lei Lu  Is a corresponding author
  1. A*STAR, Singapore, Singapore
  2. Nanyang Technological University, Singapore

Abstract

The hallmark event of the canonical transforming growth factor β (TGFβ) family signaling is the assembly of the Smad-complex, consisting of the common Smad, Smad4, and phosphorylated receptor-regulated Smads. How the Smad-complex is assembled and regulated is still unclear. Here, we report that active Arl15, an Arf-like small G protein, specifically binds to the MH2 domain of Smad4 and colocalizes with Smad4 at the endolysosome. The binding relieves the autoinhibition of Smad4, which is imposed by the intramolecular interaction between its MH1 and MH2 domains. Activated Smad4 subsequently interacts with phosphorylated receptor-regulated Smads, forming the Smad-complex. Our observations suggest that Smad4 functions as an effector and a GTPase activating protein (GAP) of Arl15. Assembly of the Smad-complex enhances the GAP activity of Smad4 toward Arl15, therefore dissociating Arl15 before the nuclear translocation of the Smad-complex. Our data further demonstrate that Arl15 positively regulates the TGFβ family signaling.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file. Source Data files have been provided.

Article and author information

Author details

  1. Meng Shi

    Skin Research Laboratory, A*STAR, Singapore, singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8119-9757
  2. Hieng Chiong Tie

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2738-8685
  3. Mahajan Divyanshu

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiuping Sun

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Yan Zhou

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Boon Kim Boh

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Leah A Vardy

    Skin Research Laboratory, A*STAR, Singapore, singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Lei Lu

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    For correspondence
    lulei@ntu.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8192-1471

Funding

Ministry of Education - Singapore (AcRF Tier1 RG35/17)

  • Meng Shi
  • Hieng Chiong Tie
  • Mahajan Divyanshu
  • Xiuping Sun
  • Yan Zhou
  • Boon Kim Boh
  • Lei Lu

Ministry of Education - Singapore (Tier2 MOE2015-T2-2-073)

  • Meng Shi
  • Hieng Chiong Tie
  • Mahajan Divyanshu
  • Xiuping Sun
  • Yan Zhou
  • Boon Kim Boh
  • Lei Lu

Ministry of Education - Singapore (MOE2018-T2-2-026)

  • Meng Shi
  • Hieng Chiong Tie
  • Mahajan Divyanshu
  • Xiuping Sun
  • Yan Zhou
  • Boon Kim Boh
  • Lei Lu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Anton M Bennett, Yale University, United States

Publication history

  1. Received: December 6, 2021
  2. Preprint posted: December 15, 2021 (view preprint)
  3. Accepted: July 12, 2022
  4. Accepted Manuscript published: July 14, 2022 (version 1)
  5. Version of Record published: August 4, 2022 (version 2)

Copyright

© 2022, Shi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Meng Shi
  2. Hieng Chiong Tie
  3. Mahajan Divyanshu
  4. Xiuping Sun
  5. Yan Zhou
  6. Boon Kim Boh
  7. Leah A Vardy
  8. Lei Lu
(2022)
Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex
eLife 11:e76146.
https://doi.org/10.7554/eLife.76146

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