An ESCRT-LEM protein surveillance system is poised to directly monitor the nuclear envelope and nuclear transport system

  1. David J Thaller
  2. Matteo Allegretti
  3. Sapan Borah
  4. Paolo Ronchi
  5. Martin Beck
  6. C Patrick Lusk  Is a corresponding author
  1. Yale School of Medicine, United States
  2. European Molecular Biology Laboratory, Germany

Abstract

The integrity of the nuclear membranes coupled to the selective barrier of nuclear pore complexes (NPCs) are essential for the segregation of nucleoplasm and cytoplasm. Mechanical membrane disruption or perturbation to NPC assembly triggers an ESCRT-dependent surveillance system that seals nuclear pores: how these pores are sensed and sealed is ill defined. Using a budding yeast model, we show that the ESCRT Chm7 and the integral inner nuclear membrane (INM) protein Heh1 are spatially segregated by nuclear transport, with Chm7 being actively exported by Xpo1/Crm1. Thus, the exposure of the INM triggers surveillance with Heh1 locally activating Chm7. Sites of Chm7 hyperactivation show fenestrated sheets at the INM and potential membrane delivery at sites of nuclear envelope herniation. Our data suggest that perturbation to the nuclear envelope barrier would lead to local nuclear membrane remodeling to promote membrane sealing. Our findings have implications for disease mechanisms linked to NPC assembly and nuclear envelope integrity.

Data availability

All data generated and analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 3.

Article and author information

Author details

  1. David J Thaller

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Matteo Allegretti

    Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Sapan Borah

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Paolo Ronchi

    Electron Microscopy Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Martin Beck

    Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7397-1321
  6. C Patrick Lusk

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    For correspondence
    patrick.lusk@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4703-0533

Funding

National Institutes of Health (GM105672)

  • C Patrick Lusk

European Molecular Biology Organization (Fellowship 6885)

  • David J Thaller

European Molecular Biology Organization (Fellowship ALTF-1389-2016)

  • Matteo Allegretti

National Institutes of Health (5T32GM007223)

  • David J Thaller

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

Reviewing Editor

  1. Greg Odorizzi, University of Colorado, United States

Publication history

  1. Received: January 17, 2019
  2. Accepted: April 2, 2019
  3. Accepted Manuscript published: April 3, 2019 (version 1)
  4. Version of Record published: April 12, 2019 (version 2)

Copyright

© 2019, Thaller 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. David J Thaller
  2. Matteo Allegretti
  3. Sapan Borah
  4. Paolo Ronchi
  5. Martin Beck
  6. C Patrick Lusk
(2019)
An ESCRT-LEM protein surveillance system is poised to directly monitor the nuclear envelope and nuclear transport system
eLife 8:e45284.
https://doi.org/10.7554/eLife.45284

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