The paracaspase MALT1 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 endolysosomal 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 with proteome-wide label-free quantification, we now report that MALT1 repression in patient-derived GSCs alters the cholesterol homeostasis, which aberrantly accumulates 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 NPC lysosomal cholesterol transporters were exhausted when MALT1 was 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.