MALT1 paracaspase controls cholesterol homeostasis in glioblastoma stem-like cells through lysosome proteome shaping

ABSTRACT: Glioblastoma stem-like cells (GSCs) compose a tumor-initiating and propagating-population, remarkably vulnerable to any variation in the stability and integrity of the endolysomal compartment. Previous work showed that the expression and activity of the paracaspase MALT1 control GSC viability via lysosomal abundance. However, the underlying mechanisms remain elusive. By combining RNAseq to quantitative proteomic analysis, we now report that MALT1 inhibition in patient-derived GSCs causes severe defects in the homeostasis of cholesterol, which aberrantly accumulated in lysosomes. This failure in cholesterol supply culminates in cell death and autophagy defects, which can be partially reverted by providing exogenous membrane-permeable cholesterol to GSCs. From a molecular standpoint, targeted lysosome proteome analysis unraveled that NPC1/2 lysosomal cholesterol transporters were exhausted when MALT1 is held in check. Accordingly, we found that hindering NPC1 and NPC2 phenocopies MALT1 inhibition. This supports the notion that GSC fitness relies on lysosomal cholesterol homeostasis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Johanna BRUCE  

LAB HEAD: Gavard Julie

PROVIDER: PXD040862 | Pride | 2025-01-16

REPOSITORIES: Pride