The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms

  1. Wenbao Hu
  2. Xiaojie Yu
  3. Zhengzhao Liu
  4. Ying Sun
  5. Xibing Chen
  6. Xin Yang
  7. Xiaofen Li
  8. Wai Kwan Lam
  9. Yuanyuan Duan
  10. Xu Cao
  11. Hermann Steller
  12. Kai Liu
  13. Pingbo Huang  Is a corresponding author
  1. Hong Kong University of Science and Technology, Hong Kong
  2. The Rockefeller University, United States

Abstract

Adenylyl cyclases (ACs) generate cAMP, a second messenger of utmost importance that regulates a vast array of biological processes in all kingdoms of life. However, almost nothing is known about how AC activity is regulated through protein degradation mediated by ubiquitination or other mechanisms. Here, we show that transcriptional regulator interacting with the PHD-bromodomain 1(TRIP-Br1, Sertad1), a newly identified protein with poorly characterized functions, acts as an adaptor that bridges the interaction of multiple AC isoforms with X-linked inhibitor of apoptosis protein (XIAP), a RING-domain E3 ubiquitin ligase. XIAP ubiquitinates a highly conserved Lys residue in AC isoforms and thereby accelerates the endocytosis and degradation of multiple AC isoforms in human cell lines. And XIAP/TRIP-Br1-mediated degradation of ACs forms part of a negative-feedback loop that controls the homeostasis of cAMP signaling in mice. Our findings reveal a previously unrecognized mechanism for degrading multiple AC isoforms and modulating the homeostasis of cAMP signaling.

Article and author information

Author details

  1. Wenbao Hu

    Division of Life Science, Hong Kong University of Science and Technology, Kwoloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiaojie Yu

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  3. Zhengzhao Liu

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  4. Ying Sun

    Division of Life Science, Hong Kong University of Science and Technology, Kowloo, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  5. Xibing Chen

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  6. Xin Yang

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaofen Li

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  8. Wai Kwan Lam

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuanyuan Duan

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  10. Xu Cao

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  11. Hermann Steller

    Strang Laboratory of Apoptosis and Cancer Biology, Howard Hughes Medical Institute,, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Kai Liu

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  13. Pingbo Huang

    Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong
    For correspondence
    bohuangp@ust.hk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4560-8760

Funding

The Kong Kong Grants Council (GRF660913)

  • Pingbo Huang

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

Ethics

Animal experimentation: All animal procedures were approved by the University Committee on Research Practices at the Hong Kong University of Science and Technology (the ethics protocol number 2014028).

Copyright

© 2017, Hu 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.

Metrics

  • 2,061
    views
  • 324
    downloads
  • 20
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Wenbao Hu
  2. Xiaojie Yu
  3. Zhengzhao Liu
  4. Ying Sun
  5. Xibing Chen
  6. Xin Yang
  7. Xiaofen Li
  8. Wai Kwan Lam
  9. Yuanyuan Duan
  10. Xu Cao
  11. Hermann Steller
  12. Kai Liu
  13. Pingbo Huang
(2017)
The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms
eLife 6:e28021.
https://doi.org/10.7554/eLife.28021

Share this article

https://doi.org/10.7554/eLife.28021

Further reading

    1. Cell Biology
    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology
    2. Developmental Biology
    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.