title: The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.|Department of Oral Biological and Medical Science, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.|Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Theo
authors.initials: T
authors.lastname: Klein
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.|Child &Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Fung
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Renner
authors.affiliation: Thermo Fisher Scientific, 355 River Oaks Parkway, San Jose, 95134 California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Blank
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.|Department of Oral Biological and Medical Science, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Antoine
authors.initials: A
authors.lastname: Dufour
authors.affiliation: Child &Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada V6T 1Z3.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Sohyeong
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Madison
authors.initials: M
authors.lastname: Bolger-Munro
authors.affiliation: Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Scurll
authors.affiliation: Child &Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada V6T 1Z3.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: John J
authors.initials: JJ
authors.lastname: Priatel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schweigler
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Samu
authors.initials: S
authors.lastname: Melkko
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gold
authors.affiliation: Thermo Fisher Scientific, 355 River Oaks Parkway, San Jose, 95134 California, USA.
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Viner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Régnier
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.|Child &Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.|Department of Oral Biological and Medical Science, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.|Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000938:Antigen-Presenting Cells; D001402:B-Lymphocytes / Q000276:immunology; D020169:Caspases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005190:Family; D005260:Female; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D015151:Immunoblotting; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018613:Microscopy, Confocal; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D014066:Palatine Tonsil; D040901:Proteomics; D016601:RNA-Binding Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000276:immunology
chemical_list: C119724:AGFG1 protein, human; D020690:GTPase-Activating Proteins; C491731:IKBKG protein, human; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; C490620:Ralbp1 protein, mouse; D014157:Transcription Factors; C504507:RBCK1 protein, human; C000607389:Rbck1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase; D020169:Caspases; C400109:MALT1 protein, human; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein