1. Biochemistry and Chemical Biology
  2. Cell Biology
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The Lamin B receptor is essential for cholesterol synthesis and perturbed by disease-causing mutations

Research Article
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Cite this article as: eLife 2016;5:e16011 doi: 10.7554/eLife.16011

Abstract

Lamin B receptor (LBR) is a polytopic membrane protein residing in the inner nuclear membrane in association with the nuclear lamina. We demonstrate that human LBR is essential for cholesterol synthesis. LBR mutant derivatives implicated in Greenberg skeletal dysplasia or Pelger-Huët anomaly fail to rescue the cholesterol auxotrophy of a LBR-deficient human cell line, consistent with a loss-of-function mechanism for these congenital disorders. These disease-causing variants fall into two classes: point mutations in the sterol reductase domain perturb enzymatic activity by reducing the affinity for the essential cofactor NADPH, while LBR truncations render the mutant protein metabolically unstable, leading to its rapid degradation at the inner nuclear membrane. Thus, metabolically unstable LBR variants may serve as long-sought-after model substrates enabling previously impossible investigations of poorly understood protein turnover mechanisms at the inner nuclear membrane of higher eukaryotes.

Article and author information

Author details

  1. Pei-Ling Tsai

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Chenguang Zhao

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elizabeth Turner

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Christian Dirk Schlieker

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    For correspondence
    christian.schlieker@yale.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Stephen G Young, University of California, Los Angeles, United States

Publication history

  1. Received: March 13, 2016
  2. Accepted: June 20, 2016
  3. Accepted Manuscript published: June 23, 2016 (version 1)
  4. Version of Record published: July 19, 2016 (version 2)

Copyright

© 2016, Tsai 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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