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Identification et caractérisation de substrats de la protéase MALT1

English title Identification and characterization of substrates of the protease MALT1
Applicant Thome-Miazza Margot
Number 166627
Funding scheme Project funding (Div. I-III)
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Biochemistry
Start/End 01.05.2016 - 30.04.2019
Approved amount 756'000.00
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Keywords (4)

immune response; signalling; protease; lymphoma

Lay Summary (German)

Lead
Die Immunantwort von B- und T-Zellen wird durch Signalwege gesteuert, die die Zellteilung und das Überleben dieser Zellen kontrollieren. In diesem Projekt wird untersucht, wie das Signalprotein MALT1 hierzu beiträgt.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Die Protease MALT1 spielt eine wesentliche Rolle in der Aktivierung von Lymphozyten und damit in der Immunantwort.  Die Aktivität von MALT1 ist normalerweise präzise kontrolliert.  In humanen B-Zell-Lymphomen kann es jedoch durch genetische Mutationen zu einer permanenten Aktivierung von MALT1 kommen, die das Tumorzell-Wachstum fördert.

Wir haben vor einigen Jahren die Protease-Aktivität von MALT1 entdeckt und dann die Proteine BCL10 und RelB als Substrate von MALT1 identifiziert.  Wie genau MALT1 die Immunantwort kontrolliert, und welche weiteren Substrate von MALT1 geschnitten werden, ist jedoch noch unbekannt.  In diesem Projekt werden wir zunächst ein kürzlich neu identifiziertes Substrat von MALT1 charakterisieren, und dann weitere MALT1 Substrate durch massenspektrometrische Versuche identifizieren.  Dadurch soll die genaue biologische Funktion von MALT1 weiter aufgeklärt werden.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Durch die Erforschung der physiologischen Funktion neuer MALT1 Substrate wollen wir dazu beitragen, neue immunologische Therapieansätze zu fördern.  Inhibitoren von MALT1, die momentan in der Entwicklung sind, hemmen effizient die Aktivierung von Lymphozyten in vitro und im Tierversuch.  Daher könnten solche Inhibitoren therapeutisch für die Behandlung von Autoimmun-Erkrankungen, Verhinderung von Transplantat-Abstossungen und die Hemmung des Lymphomwachstums nützlich sein. 

Direct link to Lay Summary Last update: 31.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia
Luong-Gardiol Noemie, Siddiqui Imran, Pizzitola Irene, Jeevan-Raj Beena, Charmoy Mélanie, Huang Yun, Irmisch Anja, Curtet Sara, Angelov Georgi S., Danilo Maxime, Juilland Mélanie, Bornhauser Beat, Thome Margot, Hantschel Oliver, Chalandon Yves, Cazzaniga Gianni, Bourquin Jean-Pierre, Huelsken Joerg, Held Werner (2019), γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia, in Cancer Cell, 35(4), 649-663.e10.
CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17–Mediated Psoriasiform Skin Inflammation In Vivo
Mellett Mark, Meier Barbara, Mohanan Deepa, Schairer Rebekka, Cheng Phil, Satoh Takashi K., Kiefer Betina, Ospelt Caroline, Nobbe Stephan, Thome Margot, Contassot Emmanuel, French Lars E. (2018), CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17–Mediated Psoriasiform Skin Inflammation In Vivo, in Journal of Investigative Dermatology, 138(9), 2010-2023.
Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma
Battistello Elena, Katanayeva Natalya, Dheilly Elie, Tavernari Daniele, Donaldson Maria C., Bonsignore Luca, Thome Margot, Christie Amanda L., Murakami Mark A., Michielin Olivier, Ciriello Giovanni, Zoete Vincent, Oricchio Elisa (2018), Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma, in Blood, 131(21), 2345-2356.
A role for MALT1 activity in Kaposi’s sarcoma-associated herpes virus latency and growth of primary effusion lymphoma
Bonsignore L, Passelli K, Pelzer C, Perroud M, Konrad A, Thurau M, Stürzl M, Dai L, Trillo-Tinoco J, Del Valle L, Qin Z, Thome M (2017), A role for MALT1 activity in Kaposi’s sarcoma-associated herpes virus latency and growth of primary effusion lymphoma, in Leukemia, 31(3), 614-624.
The paracaspase MALT1: biological function and potential for therapeutic inhibition
Jaworski Maike, Thome Margot (2016), The paracaspase MALT1: biological function and potential for therapeutic inhibition, in Cellular and Molecular Life Sciences, 73(3), 459-473.

Collaboration

Group / person Country
Types of collaboration
Dr. Georg Lenz, University of Münster, Germany Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Drs. Pedro Romero and Alena Donda, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Elisa Orecchio, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Manfredo Quadroni, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Drs. Gareth Hall and Mark Carr, University of Leicester Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Drs. Mark Mellet and Lars French, UZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Werner Held, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBO workshop "Lymphocyte signaling" Talk given at a conference MALT1 protease activity in the immune response and lymphomagenesis 28.08.2018 Pontignano (Siena), Italy Ubezzi Ivana; Thome-Miazza Margot;
EMBO workshop "Lymphocyte signaling" 2016 Talk given at a conference NF-κB and lymphoma development 07.09.2016 Siena, Italy Thome-Miazza Margot;
ILSG Lymphoma meeting Talk given at a conference Antigen receptor signaling and lymphoid malignancies 09.05.2016 Lausanne, Switzerland Thome-Miazza Margot;


Self-organised

Title Date Place
ASH conference: Lymphoma Biology 18.06.2016 Colorado Springs, United States of America

Associated projects

Number Title Start Funding scheme
146245 Analyse de la fonction moléculaire et physiologique de la protéase MALT1 01.05.2013 Project funding (Div. I-III)
147620 Functional analysis of altered transcriptional pathways in diffuse large B-cell lymphoma of the ABC subtype 01.01.2014 Sinergia
102880 Analysis of the signaling pathway regulating T-cell receptor-induced NF-kB activation and lymphocyte proliferation 01.05.2004 SNSF Professorships
129711 Analyse du rôle de la protéase MALT1 dans l'activation et la prolifération des lymphocytes 01.05.2010 Project funding (Div. I-III)
102880 Analysis of the signaling pathway regulating T-cell receptor-induced NF-kB activation and lymphocyte proliferation 01.05.2004 SNSF Professorships
184749 Identification of NF-kB-independent functions of the protease MALT1 01.05.2019 Project funding (Div. I-III)

Abstract

The protease MALT1 and its binding partners, CARMA1 and BCL10, form a complex of signaling proteins (also called the CBM complex) that is essential for the activation of the NF-?B and AP-1 transcriptional pathways in antigen-stimulated lymphocytes (Rosebeck et al., 2011; Thome et al., 2010). Genetic evidence from MALT1 knock-out mice supports the idea that MALT1 is required for the efficient generation of the adaptive immune response (Ruefli-Brasse et al., 2003; Ruland et al., 2003). Hyperactivation of this signaling pathway through activating CARMA1 mutations, on the other hand, has been associated with the development of BENTA (B-cell expansion with NF-?B and T-cell anergy) syndrome in humans (Snow et al., 2012). In addition, oncogenic activation of MALT1 has been correlated with the formation of human B-cell lymphomas of the mucosa-associated lymphoid tissue (so-called MALT lymphomas), diffuse large B-cell lymphomas (DLBCL) and mantle cell lymphomas (Hailfinger et al., 2014; Rosebeck et al., 2011). A few years ago, we have uncovered that MALT1 has protease activity that is transiently induced in activated lymphocytes, and we have identified BCL10 and RelB as MALT1 substrates that control different aspects of lymphocyte activation (Hailfinger et al., 2011; Rebeaud et al., 2008). We could show that the viability and proliferation of B-cell lines derived from the ABC subtype of DLBCL critically depends on constitutive oncogenic MALT1 activity and the cleavage of RelB (Hailfinger et al., 2009; Hailfinger et al., 2011). Moreover, through generation of mice expressing a catalytically inactive form of MALT1, we have recently demonstrated a key role for MALT1’s protease activity in lymphocyte activation, but also in the generation of natural regulatory T cells, since these mice have a combined immunodeficiency/autoimmunity phenotype (Jaworski et al., 2014). Thus, the protease activity of MALT1 plays a key role in the immune response and the generation of lymphomas. However, the exact mechanism by which MALT1 controls immune responses, and the full elucidation of its relevant substrates remain challenging tasks. Here, we propose to (1) further characterize a recently identified MALT1 substrate in detail, by analyzing the functional consequences of its cleavage in primary lymphocytes and lymphoma cell lines and (2) to explore and validate novel candidate MALT1 substrates by proteomic approaches, in order to uncover unexplored aspects of MALT1-dependent lymphocyte biology.Through the elucidation of the physiological roles of these newly uncovered MALT1 substrates, we expect to significantly contribute to the understanding of the mechanisms that control normal lymphocyte activation and its deregulation in autoimmune diseases or lymphomas.
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