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.
In humans, mutations in the gene that encodes a protein called Lamin B receptor can lead to diseases ranging from harmless anomalies of blood cells to fatal developmental defects. The severity of the disease depends on the nature of the specific mutation, and whether one or both copies of the gene are affected. Lamin B receptor – or LBR for short – is found at the envelope that surrounds the cell’s nucleus and was previously proposed to anchor this envelope to an underlying scaffold to provide it with support. LBR can also catalyze a chemical reaction involved in producing cholesterol – an essential component of cell membranes. However, this enzymatic activity was assumed to be less important because a second enzyme named TM7SF2 can perform the same reaction. Thus, it was not clear – at the molecular level – why the mutations in this gene lead to a variety of diseases.
All disease-causing mutations map to the part of LBR that is responsible for its enzymatic activity. This fact motivated Tsai, Zhao et al. to reassess the importance of LBR for the production of cholesterol. The experiments revealed that many human cells that can be grown in the laboratory strictly depend on LBR to produce cholesterol. As such, these findings challenge the previous assumption that TM7SF2 can compensate for the loss of LBR’s activity and sustain cholesterol synthesis.
Tsai, Zhao et al. also discovered that all known disease-causing mutations strongly perturb LBR’s ability to engage in cholesterol synthesis, albeit through different mechanisms. Some mutations interfered with the enzyme ability to bind with an essential molecule or cofactor that is required to catalysis; others led to LBR rapidly degrading at the nuclear envelope.
It was previously not known that proteins could be degraded at the inner membrane of the nuclear envelope of mammalian cells, and LBR mutants may turn out to be useful tools to investigate how this happens in future. Further studies could also test if other diseases caused by mutations in proteins found in the nuclear envelope act in similar ways, or if mutations in these proteins inhibit the nucleus’s protein disposal machinery.