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Analyse du rôle de la protéase MALT1 dans l'activation et la prolifération des lymphocytes

English title Analysis of the role of the protease MALT1 in lymphocyte activation and proliferation
Applicant Thome-Miazza Margot
Number 129711
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 01.05.2010 - 30.04.2013
Approved amount 537'000.00
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All Disciplines (2)

Discipline
Biochemistry
Immunology, Immunopathology

Keywords (7)

immune response; NF-kB; lymphoma; signalling; lymphocyte activation; protease; proliferation

Lay Summary (English)

Lead
Lay summary
Upon infection or detection of cancer cells, lymphocytes become activated and proliferate rapidly to fight the disease. The initiation of this immune response critically depends on intracellular signalling events that rapidly activate the lymphocyte and promote its proliferation. CARMA1, BCL10 and MALT1 are three recently identified signalling proteins that play an essential role in lymphocyte activation and proliferation. Mice deficient in any of these three proteins show impaired immune responses of mature T- and B-lymphocytes and are thus severely immunodeficient. In contrast, mutations or abnormal expression levels of these proteins have been associated with excessive lymphocyte proliferation and development of lymphoid cancers (lymphomas) in humans. Research in our laboratory has recently led to the identification of a protease activity for MALT1 that is transiently induced in activated lymphocytes in a CARMA1- and BCL10- dependent manner (Rebeaud et al., Nature Immunol (2008)). Moreover, we have developed a cell-permeable inhibitor for MALT1 that leads to impaired T-cell activation in vitro and dramatically reduced cellular proliferation of B-cell lines derived from human diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, which showed constitutive MALT1 protease activity (Hailfinger et al., PNAS (2009)). Thus, the protease activity of MALT1 might be a suitable drug target for immunomodulation and/or for the treatment of particular subtypes of human lymphomas characterized by constitutive MALT1 activity. The above-mentioned findings suggest that the protease activity of MALT1 is essential for the control of lymphocyte proliferation, but the underlying molecular mechanism remains poorly understood. It is particularly unclear how the protease activity of MALT1 is initiated and terminated, which substrate proteins are cleaved by MALT1 and how cleavage of these substrates controls lymphocyte activation and proliferation. Through the study of these open questions, we hope to contribute to the understanding of the molecular mechanisms that control lymphocyte activation under physiological conditions and under pathological circumstances that are associated with autoimmune diseases or lymphomas. A better comprehension of these mechanisms could potentially allow the rational design of MALT1-inhibiting drugs with immunosuppressive or anti-lymphoma activity.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
PKCθ/β and CYLD Are Antagonistic Partners in the NFκB and NFAT Transactivation Pathways in Primary Mouse CD3+ T Lymphocytes
Thuille N, Wachowicz K, Hermann-Kleiter N, Kaminski S, Fresser F, Lutz-Nicoladoni C, Leitges M, Thome M, Massoumi R, Baier G (2013), PKCθ/β and CYLD Are Antagonistic Partners in the NFκB and NFAT Transactivation Pathways in Primary Mouse CD3+ T Lymphocytes, in PLoS ONE, 8(1), x.
The protease activity of the paracaspase MALT1 is controlled by monoubiquitination.
Pelzer Christiane, Cabalzar Katrin, Wolf Annette, Gonzalez Montserrat, Lenz Georg, Thome Margot (2013), The protease activity of the paracaspase MALT1 is controlled by monoubiquitination., in Nature immunology, 14(4), 337-45.
MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma.
Wenzel S-S, Grau M, Mavis C, Hailfinger S, Wolf A, Madle H, Deeb G, Dörken B, Thome M, Lenz P, Dirnhofer S, Hernandez-Ilizaliturri F J, Tzankov A, Lenz G (2012), MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma., in Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 21.
The NF-κB signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles.
Marion Sabrina, Mazzolini Julie, Herit Floriane, Bourdoncle Pierre, Kambou-Pene Nadège, Hailfinger Stephan, Sachse Martin, Ruland Jürgen, Benmerah Alexandre, Echard Arnaud, Thome Margot, Niedergang Florence (2012), The NF-κB signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles., in Developmental cell, 23(5), 954-67.
IKK alpha takes control of canonical NF-kappa B activation
Pelzer C, Thome M (2011), IKK alpha takes control of canonical NF-kappa B activation, in NATURE IMMUNOLOGY, 12(9), 815-816.
Individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis.
Mühlethaler-Mottet A, Flahaut M, Bourloud K Balmas, Nardou K, Coulon A, Liberman J, Thome M, Gross N (2011), Individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis., in Cell death & disease, 2, 125-125.
Malt1-dependent RelB cleavage promotes canonical NF-kappa B activation in lymphocytes and lymphoma cell lines
Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton JE, Guzzardi M, Decaillet C, Grau M, Dorken B, Lenz P, Lenz G, Thome M (2011), Malt1-dependent RelB cleavage promotes canonical NF-kappa B activation in lymphocytes and lymphoma cell lines, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 108(35), 14596-14601.
Antigen Receptor Signaling to NF-kappa B via CARMA1, BCL10, and MALT1
Thome M, Charton JE, Pelzer C, Hailfinger S (2010), Antigen Receptor Signaling to NF-kappa B via CARMA1, BCL10, and MALT1, in COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2(9), 1-16.

Collaboration

Group / person Country
Types of collaboration
Institut Curie France (Europe)
- Publication
Universität Innsbruck Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Charité Universitätsmedizin Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
7th Conference on Experimental and translational Oncology Talk given at a conference The role of the MALT1 protease activity in lymphocyte activation and lymphoma development 20.04.2013 Portoroz, Slovenia Thome-Miazza Margot;
European Congress of Immunology Talk given at a conference The role of the paracaspase MALT1 in adaptive immunity and lymphoma 05.09.2012 Glasgow, Great Britain and Northern Ireland Thome-Miazza Margot;
Swiss Apoptosis Meeting Talk given at a conference The role of the paracaspase MALT1 in adaptive immunity and lymphoma 20.08.2012 Bern, Switzerland Thome-Miazza Margot;
Annual meeting of the research groups of the Faculties of Biology and Medicine of Lausanne and Geneva Talk given at a conference The role of the protease MALT1 in adaptive immunity and lymphoma 19.07.2012 Changins, Switzerland Thome-Miazza Margot;
Keystone conference “NF-κB signaling and Biology – from Bench to Bedside” Talk given at a conference The role of the protease MALT1 in adaptive immunity and lymphoma 18.03.2012 Whistler, Canada Thome-Miazza Margot;
SFB854 International Symposium “Molecular Organisation of Immune Cell Communication” Talk given at a conference The role of the protease MALT1 in lymphocyte activation and lymphoma development 23.09.2011 Magdeburg, Germany Thome-Miazza Margot;
Annual Congress of the Swiss Society of Allergy and Immunology Talk given at a conference Signaling pathways for lymphocyte activation and survival 17.03.2011 Lugano, Switzerland Thome-Miazza Margot;


Patents

Title Date Number Inventor Owner
Malt1 Specific Cleavage in Assay and Screening Method 12.04.2013 EP 2153231 B1

Associated projects

Number Title Start Funding scheme
102880 Analysis of the signaling pathway regulating T-cell receptor-induced NF-kB activation and lymphocyte proliferation 01.05.2004 SNSF Professorships
146245 Analyse de la fonction moléculaire et physiologique de la protéase MALT1 01.05.2013 Project funding (Div. I-III)
166627 Identification et caractérisation de substrats de la protéase MALT1 01.05.2016 Project funding (Div. I-III)

Abstract

CARMA1, BCL10 and MALT1 are three recently identified proteins that play an essential role in T-cell receptor- and B-cell receptor-induced lymphocyte activation and proliferation. Mice deficient in any of these three proteins show impaired antigen-dependent responses of mature T- and B-lymphocytes and are severely immunodeficient. In humans, chromosomal translocation and abnormal expression of the genes encoding BCL10 and MALT1 have been associated with constitutive activation of the transcription factor NF-?B and the formation of B-cell lymphomas of the mucosa-associated lymphoid tissue (so-called MALT lymphomas). Morerover, oncogenic mutations in CARMA1 have been identified in patients suffering from diffuse large B-cell lymphomas (DLBCL) of the activated B-cell subtype (ABC-DLBCL). We and others have recently identified a protease activity for MALT1 that is transiently induced in activated lymphocytes in a CARMA1- and BCL10- dependent manner. Moreover, we have developed a cell-permeable inhibitor for MALT1 that leads to impaired T-cell activation in vitro and dramatically reduced cellular proliferation of B-cell lines derived from ABC-DLBCL, which showed constitutive MALT1 protease activity. Thus, the protease activity of MALT1 might be a suitable drug target for immunomodulation and/or for the treatment of particular subtypes of human lymphomas characterized by constitutive MALT1 activity. The above-mentioned findings suggest that the protease activity of MALT1 is essential for the control of lymphocyte proliferation, but the underlying molecular mechanism remains poorly understood. It is particularly unclear how the protease activity of MALT1 is initiated and terminated, which substrate proteins are cleaved by MALT1 and how cleavage of these substrates controls lymphocyte activation and proliferation. Here we propose to address these issues by (1) the identification of positive and negative regulators of MALT1 activity, (2) the characterization of the function of three recently identified MALT1 substrates and (3) the identification of novel substrates of MALT1.By the elucidation of MALT1-dependent signaling events, we expect to significantly contribute to the understanding of the molecular mechanisms that control lymphocyte activation under physiological conditions and under pathological circumstances that are associated with autoimmune diseases or lymphomas. Moreover, a better comprehension of these mechanisms could potentially allow the rational design of MALT1-inhibiting drugs with immunosuppressive or anti-lymphoma activity.
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