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Analyse de la fonction moléculaire et physiologique de la protéase MALT1

English title Analysis of the molecular and physiological function of the protease MALT1
Applicant Thome-Miazza Margot
Number 146245
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 01.05.2013 - 30.04.2016
Approved amount 638'880.00
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Keywords (4)

immune response; NF-kB; signalling; lymphoma

Lay Summary (German)

Lead
Dieses Projekt erforscht die molekulare Funktion der Protease MALT1, die eine essentielle Rolle in der Proliferation von Lymphozyten spielt. Wir verwenden biochemische und genetische Ansätze um die Funktion von MALT1 zu erforschen und zu klären, ob eine Hemmung der MALT1 Aktivität nützlich sein könnte für die therapeutische Immunsuppression und die Behandlung von humanen Lymphomen.
Lay summary

Die Aktivierung und Proliferation von Lymphozyten erfordert einen Transkriptionsfaktor, NF-kB, der die Expression von Genen kontrolliert welche für die Proliferation und das Überleben von Lymphozyten wichtig sind.   Wir interessieren uns für die Protease MALT1, die eine essentielle Rolle in der NF-kB Aktivierung spielt.  Unsere Forschungsergebnisse haben gezeigt, dass eine Hemmung der MALT1 Aktivität von therapeutischem Nutzen für die Immunsuppression und die Behandlung spezifischer Lymphome sein könnte. Die genauen Mechanismen der MALT1-vermittelten Lymphozyten-Proliferation und die Erkundung der MALT1 Substrate bleiben jedoch grosse Herausforderungen für unsere Forschungsarbeit, die wir mit biochemischen und genetischen Ansätzen klären wollen.

Durch die Erforschung der molekularen und physiologischen Rolle von MALT1 möchten wir zum grundlegenden Verständnis der Mechanismen der Lymphozyten-Proliferation, der Entwicklung von Autoimmunerkrankungen und Lymphomen beitragen.  Ein besseres Verständnis dieser Mechanismen könnte zur Entwicklung rationaler MALT1 Inhibitoren für therapeutische Zwecke führen.

Direct link to Lay Summary Last update: 10.04.2013

Lay Summary (English)

Lead
This project addresses the molecular function of a protease, MALT1, that is essential for the proliferation of lymphocytes. We use biochemical and genetic approaches to elucidate the function of MALT1 and to clarify whether MALT1 inhibition could be useful for therapeutic immunosuppression and treatment of human lymphomas.
Lay summary

The activation and proliferation of lymphocytes requires a transcription factor, NF-kB, which controls the expression of proliferation- and survival-promoting genes.  We are interested in a protease, MALT1, that is essential for the activation of NF-kB in antigen-stimulated lymphocytes.  Our research has identified the protease activity of MALT1 as a candidate drug target for immunomodulation and for the treatment of particular subtypes of human lymphomas that are characterized by constitutive MALT1 activity.  However, the exact mechanism by which MALT1 promotes lymphocyte proliferation and the full elucidation of its substrates remain challenging tasks that we wish to address here using biochemical and genetic approaches.

By the elucidation of the molecular and physiological role of MALT1, we expect to significantly contribute to the understanding of the mechanisms that control normal lymphocyte activation and its deregulation in 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.

Direct link to Lay Summary Last update: 10.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The paracaspase MALT1: biological function and potential for therapeutic inhibition
Jaworski M. and Thome M. (2016), The paracaspase MALT1: biological function and potential for therapeutic inhibition, in Cell. Mol. Life Sci., 73, 459.
Detection and measurement of paracaspase MALT1 activity
Hailfinger S. et al. (2014), Detection and measurement of paracaspase MALT1 activity, in Methods Mol. Biol., 1133, 177.
MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.
Beans T. et al (2014), MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes., in PLoS One, 9, e103774.
Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity
Jaworski M. et al. (2014), Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity, in EMBO J., 33, 2765.
NOTCH1 Can Initiate NF-κB Activation via Cytosolic Interactions with Components of the T Cell Signalosome.
Shin H.M. et al. (2014), NOTCH1 Can Initiate NF-κB Activation via Cytosolic Interactions with Components of the T Cell Signalosome., in Front. Immunol., 5, 249.
Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase
Hailfinger S. et al. (2014), Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase, in Curr. Opin. Chem. Biol., 23, 47-55.
IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL
Nogai H. et al (2013), IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL, in Blood, 122, 2242-2250.
Monoubiquitination and activity of the paracaspase MALT1 requires glutamate 549 in the dimerization interface
Cabalzar K. et al (2013), Monoubiquitination and activity of the paracaspase MALT1 requires glutamate 549 in the dimerization interface, in PLoS One, 8, e72051.

Collaboration

Group / person Country
Types of collaboration
Dr. Georg Lenz / Charité, Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Ben Marsland / CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Dela Golshayan / CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Olivier Gaide / CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Thijs Baens / University of Ghent Belgium (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
Jürg Tschopp Memorial Symposium Talk given at a conference Malt1 signaling in the immune response and lymphomagenesis 27.04.2016 Montreux, Switzerland Schairer Rebekka; Ubezzi Ivana; Gonzalez Montserrat; Décaillet Chantal; Thome-Miazza Margot;
Cold Spring Harbor Lab Meeting “Fundamental immunology and its therapeutic potential” Talk given at a conference Role of the protease MALT1 in the immune system 14.04.2015 Cold Spring Harbor, United States of America Thome-Miazza Margot;
European NF-kB workshop Talk given at a conference MALT1-dependent lymphoid signaling and B-cell malignancy 07.10.2014 Pitlochry, Scottland, Great Britain and Northern Ireland Thome-Miazza Margot;
ASH meeting on Lymphoma Biology Talk given at a conference MALT1-dependent lymphoid signaling and B-cell malignancy 11.08.2014 Colorado Springs, United States of America Thome-Miazza Margot;
Keystone conference: "The NF-kB System in Health and Disease" Talk given at a conference MALT1-dependent lymphoid signaling and B-cell malignancy 26.02.2014 Keystone, Colorado, United States of America Thome-Miazza Margot;


Associated projects

Number Title Start Funding scheme
166627 Identification et caractérisation de substrats de la protéase MALT1 01.05.2016 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
129711 Analyse du rôle de la protéase MALT1 dans l'activation et la prolifération des lymphocytes 01.05.2010 Project funding (Div. I-III)
150799 Advanced analysis of the function of single cells using flow imaging. 01.12.2013 R'EQUIP

Abstract

The activation and proliferation of lymphocytes requires the antigen receptor-mediated activation of a transcription factor, NF-kB, which controls the expression of proliferation- and survival-promoting genes. CARMA1, BCL10 and MALT1 form a complex of signaling proteins (also called the CBM complex) that plays an essential role in the activation of the NF-kB pathway in antigen-stimulated lymphocytes (Rosebeck et al., 2011b; Thome et al., 2010). Genetic evidence from knock-out mice supports the idea that each of the three CBM proteins is required for the efficient generation of the adaptive immune response. There is also good evidence for an oncogenic role of the CBM proteins in the formation of human B-cell lymphomas of the mucosa-associated lymphoid tissue (so-called MALT lymphomas) and diffuse large B-cell lymphomas (DLBCL) (Rosebeck et al., 2011b). We have recently shown that MALT1 has protease activity that is transiently induced in activated lymphocytes in a CARMA1- and BCL10- dependent manner, 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). Moreover, we could show that the viability and proliferation of B-cell lines derived from ABC-DLBCL critically depends on constitutive oncogenic MALT1 activity and the cleavage of RelB (Hailfinger et al., 2009; Hailfinger et al., 2011). Collectively, these findings have identified the protease activity of MALT1 as a candidate drug target for immunomodulation and for the treatment of particular subtypes of human lymphomas characterized by constitutive MALT1 activity. However, the exact mechanism by which MALT1 promotes lymphocyte proliferation, and the full elucidation of its relevant substrates remain challenging tasks. Here we propose to address these issues by (1) the identification and characterization of new MALT1 substrates, (2) the identification of MALT1 regulators and (3) the characterization of the immune phenotype of mice expressing a catalytically inactive version of MALT1.By the elucidation of the molecular and physiological role of MALT1, we expect to significantly contribute to the understanding of the mechanisms that control normal lymphocyte activation and its deregulation in 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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