1. Cell Biology
Download icon

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
Research Article
  • Cited 9
  • Views 1,658
  • Annotations
Cite this article as: eLife 2017;6:e28021 doi: 10.7554/eLife.28021

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).

Reviewing Editor

  1. Volker Dötsch, J.W. Goethe-University, Germany

Publication history

  1. Received: April 22, 2017
  2. Accepted: June 28, 2017
  3. Accepted Manuscript published: June 28, 2017 (version 1)
  4. Version of Record published: July 10, 2017 (version 2)
  5. Version of Record updated: July 11, 2017 (version 3)

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

  • 1,658
    Page views
  • 268
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Neuroscience

    Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

    Rene Solano Fonseca et al.
    Research Article Updated

    Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

    1. Biochemistry and Chemical Biology
    2. Cell Biology

    Endothelial pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure in mice

    Zdravka Daneva et al.
    Research Article Updated

    Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.

    1. Cell Biology

    Ectocytosis prevents accumulation of ciliary cargo in C. elegans sensory neurons

    Adria Razzauti, Patrick FM Laurent
    Research Article

    Cilia are sensory organelles protruding from cell surfaces. Release of Extracellular Vesicles (EVs) from cilia was previously observed in mammals, Chlamydomonas, and in male C. elegans. Using the EV marker TSP-6 (an ortholog of mammalian CD9) and other ciliary receptors, we show that EVs are formed from ciliated sensory neurons in C. elegans hermaphrodites. Release of EVs is observed from two ciliary locations: the cilia tip and/or Periciliary Membrane Compartment (PCMC). Outward budding of EVs from the cilia tip leads to their release into the environment. EVs budding from the PCMC are concomitantly phagocytosed by the associated glial cells. To maintain cilia composition, a tight regulation of cargo import and removal is achieved by the action of Intra-Flagellar Transport (IFT). Unbalanced IFT due to cargo overexpression or mutations in the IFT machinery leads to local accumulation of ciliary proteins. Disposal of excess ciliary proteins via EVs reduces their local accumulation and exports them to the environment and/or to the glia associated to these ciliated neurons. We suggest that EV budding from cilia subcompartments acts as a safeguard mechanism to remove deleterious excess of ciliary material.