1. Cell Biology
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KLHL41 stabilizes skeletal muscle sarcomeres by nonproteolytic ubiquitination

  1. Andres Ramirez-Martinez
  2. Bercin Kutluk Cenik
  3. Svetlana Bezprozvannaya
  4. Beibei Chen
  5. Rhonda Bassel-Duby  Is a corresponding author
  6. Ning Liu  Is a corresponding author
  7. Eric Olson  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
Research Article
  • Cited 25
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Cite this article as: eLife 2017;6:e26439 doi: 10.7554/eLife.26439

Abstract

Maintenance of muscle function requires assembly of contractile proteins into highly organized sarcomeres. Mutations in Kelch-like protein 41 (KLHL41) cause nemaline myopathy, a fatal muscle disorder associated with sarcomere disarray. We generated KLHL41 mutant mice, which display lethal disruption of sarcomeres and aberrant expression of muscle structural and contractile proteins, mimicking the hallmarks of the human disease. We show that KLHL41 is poly-ubiquitinated and acts, at least in part, by preventing aggregation and degradation of Nebulin, an essential component of the sarcomere. Furthermore, inhibition of KLHL41 poly-ubiquitination prevents its stabilization of NEB, suggesting a unique role for ubiquitination in protein stabilization. These findings provide new insights into the molecular etiology of nemaline myopathy and reveal a mechanism whereby KLHL41 stabilizes sarcomeres and maintains muscle function by acting as a molecular chaperone. Similar mechanisms for protein stabilization likely contribute to the actions of other Kelch proteins.

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Article and author information

Author details

  1. Andres Ramirez-Martinez

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bercin Kutluk Cenik

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Svetlana Bezprozvannaya

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Beibei Chen

    Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rhonda Bassel-Duby

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    rhonda.bassel-duby@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
  6. Ning Liu

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Ning.Liu@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
  7. Eric Olson

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Eric.Olson@UTSouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1151-8262

Funding

National Institutes of Health (HL130253 HL077439 DK099653 AR067294)

  • Eric Olson

Welch Foundation (1-0025)

  • Eric Olson

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (2015-100829) of the University of Texas Southwestern Medical Center. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Texas Southwestern Medical Center (NIH OLAW Assurance Number D16-00296 ).

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: March 1, 2017
  2. Accepted: August 4, 2017
  3. Accepted Manuscript published: August 9, 2017 (version 1)
  4. Accepted Manuscript updated: August 24, 2017 (version 2)
  5. Version of Record published: September 7, 2017 (version 3)

Copyright

© 2017, Ramirez-Martinez 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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