SOAP: Signaling in Oncogenesis, Angiogenesis, and Permeability
On the ground of our interests for molecular piracy exerted by tumor cells to survive, adapt and remodel their environment, we explore the signaling mechanisms involved in non-oncogene addiction and loss of vascular homeostasis.
Research Highlights
The centrosomal protein 131 participates in the regulation of mitochondrial apoptosis
Renaud CCN, Trillet K, Jardine J, Merlet L, Renoult O, Laurent-Blond M, Catinaud Z, Pecqueur C, Gavard J, Bidere N.
Comms Biol 2023
Centriolar satellites are multiprotein aggregates that orbit the centrosome and govern centrosome homeostasis and primary cilia formation. In contrast to the scaffold PCM1, which nucleates centriolar satellites and has been linked to microtubule dynamics, autophagy, and intracellular trafficking, the functions of its interactant CEP131 beyond ciliogenesis remain unclear. Using a knockout strategy in a non-ciliary T-cell line, we report that, although dispensable for centriolar satellite assembly, CEP131 participates in optimal tubulin glycylation and polyglutamylation, and microtubule regrowth. Our unsupervised label-free proteomic analysis by quantitative mass spectrometry further uncovered mitochondrial and apoptotic signatures. CEP131-deficient cells showed an elongated mitochondrial network. Upon cell death inducers targeting mitochondria, knockout cells displayed delayed cytochrome c release from mitochondria, subsequent caspase activation, and apoptosis. This mitochondrial permeabilization defect was intrinsic, and replicable in vitro with isolated organelles. These findings extend CEP131 functions to life-and-death decisions and propose ways to interfere with mitochondrial apoptosis.
Maghe C, Trillet K, Andre-Gregoire G, Kerherve M, Merlet L, Jacobs KA, Schauer K, Bidere N, Gavard J
Cell Rep 2024
Glioblastoma stem-like cells (GSCs) compose a tumor-initiating and -propagating population remarkably vulnerable to variation in the stability and integrity of the lysosomal compartment. Previous work has shown that the expression and activity of the paracaspase MALT1 control GSC viability via lysosome abundance. However, the underlying mechanisms remain elusive. By combining RNA sequencing (RNA-seq) with proteome-wide label-free quantification, we now report that MALT1 repression in patient-derived GSCs alters the homeostasis of cholesterol, which accumulates in late endosomes (LEs)-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, a targeted lysosome proteome analysis unraveled that Niemann-Pick type C (NPC) lysosomal cholesterol transporters are diluted when MALT1 is impaired. Accordingly, we found that NPC1/2 inhibition and silencing partially mirror MALT1 loss-of-function phenotypes. This supports the notion that GSC fitness relies on lysosomal cholesterol homeostasis.
Funding
Agence Nationale pour la Recherche
Canceropole GO
Fondation ARC
Fondation de France
Institut National du Cancer
Ligue contre le Cancer
Region Pays-de-la-Loire
