1. Cell Biology
Download icon

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
  6. Ning Liu  Is a corresponding author
  7. Eric N Olson  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
Research Article
  • Cited 19
  • Views 1,778
  • Annotations
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.

Data availability

The following data sets were generated

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
    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 N 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 N Olson

Welch Foundation (1-0025)

  • Eric N 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.

Metrics

  • 1,778
    Page views
  • 365
    Downloads
  • 19
    Citations

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

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)

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Asha Mary Joseph et al.
    Research Article

    Translesion synthesis (TLS) is a highly conserved mutagenic DNA lesion tolerance pathway, which employs specialized, low-fidelity DNA polymerases to synthesize across lesions. Current models suggest that activity of these polymerases is predominantly associated with ongoing replication, functioning either at or behind the replication fork. Here we provide evidence for DNA damage-dependent function of a specialized polymerase, DnaE2, in replication-independent conditions. We develop an assay to follow lesion repair in non-replicating Caulobacter and observe that components of the replication machinery localize on DNA in response to damage. These localizations persist in the absence of DnaE2 or if catalytic activity of this polymerase is mutated. Single-stranded DNA gaps for SSB binding and low-fidelity polymerase-mediated synthesis are generated by nucleotide excision repair, as replisome components fail to localize in the absence of NER. This mechanism of gap-filling facilitates cell cycle restoration when cells are released into replication-permissive conditions. Thus, such cross-talk (between activity of NER and specialized polymerases in subsequent gap-filling) helps preserve genome integrity and enhances survival in a replication-independent manner.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Marzia Munafò et al.
    Research Article

    The Nuclear Pore Complex (NPC) is the principal gateway between nucleus and cytoplasm that enables exchange of macromolecular cargo. Composed of multiple copies of ~30 different nucleoporins (Nups), the NPC acts as a selective portal, interacting with factors which individually license passage of specific cargo classes. Here we show that two Nups of the inner channel, Nup54 and Nup58, are essential for transposon silencing via the PIWI-interacting RNA (piRNA) pathway in the Drosophila ovary. In ovarian follicle cells, loss of Nup54 and Nup58 results in compromised piRNA biogenesis exclusively from the flamenco locus, whereas knockdowns of other NPC subunits have widespread consequences. This provides evidence that some nucleoporins can acquire specialised roles in tissue-specific contexts. Our findings consolidate the idea that the NPC has functions beyond simply constituting a barrier to nuclear/cytoplasmic exchange, as genomic loci subjected to strong selective pressure can exploit NPC subunits to facilitate their expression.