Torsins are essential, disease-relevant ATPases, but their function is unknown. Monitoring of nuclear envelope morphology after deletion of multiple Torsins or their cofactors reveals a robust inner nuclear membrane–blebbing phenotype in HeLa cells. Nucleoporins and ubiquitin are defining molecular components of these omega-shaped blebs.
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.DOI:
http://dx.doi.org/10.7554/eLife.16011.001
Background:TorsinB is an AAAϩ ATPase of unknown function. Results: ATPase-arrested TorsinB induces the formation of LULL1-enriched, luminally constricted ER membranes requiring a highly conserved C-terminal motif in TorsinB. Conclusion: Membrane structures formed by the TorsinB dominant-negative mutant are dependent on association with ATPase-activating factor LULL1. Significance: This study supports a role for TorsinB in membrane dynamics.
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