The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling

Nat Commun. 2015 Nov 3;6:8777. doi: 10.1038/ncomms9777.

Abstract

Antigen receptor signalling activates the canonical NF-κB pathway via the CARD11/BCL10/MALT1 (CBM) signalosome involving key, yet ill-defined roles for linear ubiquitination. The paracaspase MALT1 cleaves and removes negative checkpoint proteins, amplifying lymphocyte responses in NF-κB activation and in B-cell lymphoma subtypes. To identify new human MALT1 substrates, we compare B cells from the only known living MALT1(mut/mut) patient with healthy MALT1(+/mut) family members using 10-plex Tandem Mass Tag TAILS N-terminal peptide proteomics. We identify HOIL1 of the linear ubiquitin chain assembly complex as a novel MALT1 substrate. We show linear ubiquitination at B-cell receptor microclusters and signalosomes. Late in the NF-κB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-κB activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-κB pathway-first promoting activation via the CBM--then triggering HOIL1-dependent negative-feedback termination, preventing reactivation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antigen-Presenting Cells
  • B-Lymphocytes / immunology
  • Caspases / genetics*
  • Caspases / immunology
  • Caspases / metabolism
  • Family
  • Female
  • Fluorescent Antibody Technique
  • GTPase-Activating Proteins / metabolism
  • Gene Knock-In Techniques
  • Humans
  • I-kappa B Kinase / metabolism
  • Immunoblotting
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Immunoprecipitation
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leukocytes, Mononuclear
  • Lymphocytes / immunology*
  • Male
  • Mass Spectrometry
  • Mice
  • Microscopy, Confocal
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Mutation
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism
  • Nuclear Pore Complex Proteins / metabolism
  • Palatine Tonsil
  • Proteomics
  • RNA-Binding Proteins / metabolism
  • T-Lymphocytes / immunology
  • Tandem Mass Spectrometry
  • Transcription Factors
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / immunology

Substances

  • AGFG1 protein, human
  • GTPase-Activating Proteins
  • IKBKG protein, human
  • Intracellular Signaling Peptides and Proteins
  • NEMO protein, mouse
  • NF-kappa B
  • Neoplasm Proteins
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • Ralbp1 protein, mouse
  • Transcription Factors
  • RBCK1 protein, human
  • Rbck1 protein, mouse
  • Ubiquitin-Protein Ligases
  • I-kappa B Kinase
  • Caspases
  • MALT1 protein, human
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein