Biology subjects

Maghe, C.

Publications and source records attributed to Maghe, C..

4 recordsLinked to original sources

bioRxiv2023

Necrosulfonamide causes ubiquitination of PCM1 and impairs Ciliogenesis and Autophagy

Centriolar satellites are high-order assemblies, scaffolded by the protein PCM1, that gravitate as particles around the centrosome and play pivotal roles in fundamental cellular processes notably ciliogenesis and autophagy. Despite stringent control mechanisms involving phosphorylation and ubiquitination, the landscape of post-translational modifications shaping these structures remains elusive. Here, we report that necrosulfonamide (NSA), a small molecule known for binding and inactivating the pivotal effector of cell death by necroptosis MLKL, intersects with centriolar satellites, ciliogenesis, and autophagy independently of MLKL. NSA functions as a potent redox cycler and triggers the oxidation and aggregation of PCM1 alongside select partners, while minimally impacting the overall distribution of centriolar satellites. Additionally, NSA-mediated ROS production disrupts ciliogenesis and leads to the accumulation of autophagy markers, partially alleviated by PCM1 deletion. Together, these results identify PCM1 as a redox sensor protein and provide new insights into the interplay between centriolar satellites and autophagy.

cell biology↗

bioRxiv2023

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

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.

cancer biology↗

bioRxiv2021

The Necroptosis Effector MLKL drives Small Extracellular Vesicle Release and Tumour Growth in Glioblastoma

Extracellular vesicles (EVs) are lipid-based nano-sized particles that convey biological material from donor to recipient cells. They play key roles in tumour progression, notably in glioblastoma in which the subpopulation of Glioblastoma Stem-like Cells (GSCs) might represent a meaningful source of tumour-derived EVs. However, the mechanisms involved in the production and release of EVs by GSCs are still poorly understood. Here, we report the identification of MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of small EVs from GSCs. The targeting of MLKL by genetic, protein depletion or chemical approaches alters endosomal trafficking and EV release and reduces GSC expansion in vitro. This function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL triggers a reduction of both the tumour burden in xenografted mice and of the level of plasmatic EVs. This work reinforces the idea of a non-deadly role for MLKL in endosomal trafficking and suggests that interfering with EV biogenesis is a promising therapeutic option to sensitize glioblastoma cells to death.

cell biology↗

bioRxiv2019

Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-{kappa}B activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impaired autophagic flux, and culminates in lysosomal-mediated death, concomitantly with mTOR inactivation and dispersion from lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.

cell biology↗