1. Cell Biology

A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport

  1. Alberto T Gatta
  2. Louise H Wong
  3. Yves Y Sere
  4. Diana M Calderón-Noreña
  5. Shamshad Cockcroft
  6. Anant K Menon
  7. Tim P Levine  Is a corresponding author
  1. UCL Institute of Ophthalmology, United Kingdom
  2. Weill Cornell Medical College, United States
  3. University College London, United Kingdom
https://doi.org/10.7554/eLife.07253
Share this article
Cite this article
  1. Alberto T Gatta
  2. Louise H Wong
  3. Yves Y Sere
  4. Diana M Calderón-Noreña
  5. Shamshad Cockcroft
  6. Anant K Menon
  7. Tim P Levine
(2015)
A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport
eLife 4:e07253.
https://doi.org/10.7554/eLife.07253
  2. Download BibTeX
  3. Download .RIS

Abstract

Sterol traffic between the endoplasmic reticulum (ER) and plasma membrane (PM) is a fundamental cellular process that occurs by a poorly understood non-vesicular mechanism. We identified a novel, evolutionarily diverse family of ER membrane proteins with StART-like lipid transfer domains and studied them in yeast. StART-like domains from Ysp2p and its paralog Lam4p specifically bind sterols, and Ysp2p, Lam4p and their homologs Ysp1p and Sip3p target punctate ER-PM contact sites distinct from those occupied by known ER-PM tethers. The activity of Ysp2p, reflected in amphotericin-sensitivity assays, requires its second StART-like domain to be positioned so that it can reach across ER-PM contacts. Absence of Ysp2p, Ysp1p or Sip3p reduces the rate at which exogenously supplied sterols traffic from the PM to the ER. Our data suggest that these StART-like proteins act in trans to mediate a step in sterol exchange between the PM and ER.

Article and author information

Author details

  1. Alberto T Gatta

    Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Louise H Wong

    Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Yves Y Sere

    Department of Biochemistry, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Diana M Calderón-Noreña

    Department of Biochemistry, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Shamshad Cockcroft

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Anant K Menon

    Department of Biochemistry, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Tim P Levine

    Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom
    For correspondence
    tim.levine@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Gatta 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

  • 6,288
    views
  • 1,647
    downloads
  • 226
    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. Alberto T Gatta
  2. Louise H Wong
  3. Yves Y Sere
  4. Diana M Calderón-Noreña
  5. Shamshad Cockcroft
  6. Anant K Menon
  7. Tim P Levine
(2015)
A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport
eLife 4:e07253.
https://doi.org/10.7554/eLife.07253

Share this article

https://doi.org/10.7554/eLife.07253

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis

    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

    Stratification of enterochromaffin cells by single-cell expression analysis

    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

    1. Cell Biology
    2. Developmental Biology

    Lens Development: Bringing signaling complexity into focus

    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.