The Lamin B receptor is essential for cholesterol synthesis and perturbed by disease-causing mutations

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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.

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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.
Chenguang Zhao

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Elizabeth Turner

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
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.

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