1. Cell Biology
  2. Structural Biology and Molecular Biophysics
Download icon

Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels

  1. Florian Ullrich
  2. Sandy Blin
  3. Katina Lazarow
  4. Tony Daubitz
  5. Jens Peter von Kries
  6. Thomas J Jentsch  Is a corresponding author
  1. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Germany
Research Article
  • Cited 9
  • Views 2,574
  • Annotations
Cite this article as: eLife 2019;8:e49187 doi: 10.7554/eLife.49187

Abstract

Acid-sensing ion channels have important functions in physiology and pathology, but the molecular composition of acid-activated chloride channels had remained unclear. We now used a genome-wide siRNA screen to molecularly identify the widely expressed acid-sensitive outwardly-rectifying anion channel PAORAC/ASOR. ASOR is formed by TMEM206 proteins which display two transmembrane domains (TMs) and are expressed at the plasma membrane. Ion permeation-changing mutations along the length of TM2 and at the end of TM1 suggest that these segments line ASOR’s pore. While not belonging to a gene family, TMEM206 has orthologs in probably all vertebrates. Currents from evolutionarily distant orthologs share activation by protons, a feature essential for ASOR’s role in acid-induced cell death. TMEM206 defines a novel class of ion channels. Its identification will help to understand its physiological roles and the diverse ways by which anion-selective pores can be formed.

Article and author information

Author details

  1. Florian Ullrich

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1153-2040
  2. Sandy Blin

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5762-5149
  3. Katina Lazarow

    Screening Unit, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Tony Daubitz

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Jens Peter von Kries

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Thomas J Jentsch

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    For correspondence
    jentsch@fmp-berlin.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3509-2553

Funding

H2020 European Research Council (Advanced Grant VOLSIGNAL (#740537))

  • Thomas J Jentsch

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

Reviewing Editor

  1. Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany

Publication history

  1. Received: June 10, 2019
  2. Accepted: July 17, 2019
  3. Accepted Manuscript published: July 18, 2019 (version 1)
  4. Version of Record published: July 29, 2019 (version 2)

Copyright

© 2019, Ullrich 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

  • 2,574
    Page views
  • 431
    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)

  1. Further reading

Further reading

    1. Cell Biology
    Fernando R Balestra et al.
    Research Article

    TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity, including in Mulibrey patients.

    1. Cancer Biology
    2. Cell Biology
    Shima Ghoroghi et al.
    Research Article Updated

    Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivoand are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB, and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146-dependent manner.