ESPE Yearbook of Paediatric Endocrinology

Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2101671118. doi: 10.1073/pnas.2101671118

Brief Summary: This cell model study shows that cholesterol is essential for the transcriptional repressor and cell differentiation activities of brain acid soluble protein 1 (BASP1).

Cholesterol biology covers a spectrum of functions spanning from the biosynthesis of Vitamin D, bile acids and steroids, to the control of plasma membrane fluidity, protein trafficking, and signaling transduction. This study further expands this lengthy list by describing a novel function of cholesterol in the cellular nucleus, where it drives the activation of the transcriptional co-repressor Brain acid soluble protein 1 (BASP1).

BASP1 binds and inhibits the transcriptional activity of Wilms tumor 1 (WT1), a transcriptional factor best known for its association with early onset nephroblastoma. Depletion of BASP1 in adult fibroblasts replaces the requirement of three Yamanaka reprogramming factors for the induction of pluripotency, which underscores BASP1’s role in cell differentiation through WT1. The authors use both cell-free and K562 chronic myelogenous leukemia cell line-based assays, combined with immunoprecipitation and immunofluorescence, to demonstrate that BASP1 interacts with cholesterol in cell nuclei through a conserved CRAC motif. Immunodetection in cell nuclei also showed that BASP1 knock-down resulted in almost complete absence of nuclear cholesterol, suggesting nuclear BASP1 is a major reason for cholesterol being in the nucleus. They also found that BASP1 recruits cholesterol to the gene promoter regions of WT1 target genes, and that BASP1-cholesterol interaction is necessary for the control of K562 cell differentiation towards a neuronal-like phenotype. In line with this, the authors show that inhibition of cholesterol synthesis, using atorvastatin, lovastatin, or tripanarol, reduced the phorbol 12-myristate 13-acetate (PMA)-induced differentiation of K562 cells, and disruption of the CRAC domain resulted in complete inhibition of the co-repression function of BASP1.

While clinical attention nowadays focuses on systemic cholesterol metabolism and cytotoxicity of cholesterol excess because of its tight association with atherosclerotic risk, the importance of local cholesterol distribution and cellular functions is mostly overlooked. The work by Loats et al. makes a step forward in our understanding of local/cellular functions of cholesterol, by highlighting how cholesterol availability can ultimately impact cellular differentiation.