Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis

EMBO J. 2020 Jan 2;39(1):e102030. doi: 10.15252/embj.2019102030. Epub 2019 Nov 27.


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-κB 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, impairs autophagic flux, and culminates in lysosomal-mediated cell death, concomitantly with mTOR inactivation and dispersion from endo-lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.

Keywords: mTOR; MALT1; glioma; lysosome; protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Proliferation
  • Endosomes / metabolism
  • Endosomes / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology*
  • Homeostasis*
  • Humans
  • Lymphocyte Activation
  • Lysosomes / metabolism
  • Lysosomes / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / genetics
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Proteolysis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • RNA-Binding Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Associated data

  • GEO/GSE139018