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Identification of NF-kB-independent functions of the protease MALT1

English title Identification of NF-kB-independent functions of the protease MALT1
Applicant Thome-Miazza Margot
Number 184749
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 01.05.2019 - 30.04.2023
Approved amount 995'608.00
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Keywords (5)

C. elegans; immune response; signalling; protease; B-cell

Lay Summary (German)

Lead
In diesem Projekt wird untersucht, wie das Signalprotein MALT1 die Immunantwort von Lymphozyten steuert. Ausserdem wird erforscht, inwieweit MALT1-gesteuerte Prozesse in niedrigeren Lebewesen konserviert sind.
Lay summary

Die Protease MALT1 spielt eine wesentliche Rolle in der Aktivierung von Lymphozyten und damit in der Immunantwort des Menschen. Normalerweise ist die Aktivität von MALT1 präzise kontrolliert.  In bestimmten Tumoren von Lymphozyten (Lymphomen) kann es jedoch durch genetische Mutationen zu einer permanenten Aktivierung von MALT1 kommen, die das Tumorzell-Wachstum fördert. 

MALT1 ist eine Protease, die andere Proteine schneidet. Wie das Schneiden dieser Substrate die Immunantwort kontrolliert ist noch weitestgehend unerforscht.  In diesem Projekt untersuchen wir mit genetischen und molekularen Ansätzen, wie das Schneiden eines neu identifizierten Substrats die Immunantwort beeinflusst.  Parallel dazu erforschen wir evolutionär konservierte Funktionen von MALT1 in Lebewesen ohne Lymphozyten, wie dem Rundwurm C. elegans, um so noch unbekannte Funktionen von MALT1 in der Immunabwehr aufzudecken.

Direct link to Lay Summary Last update: 01.04.2019

Responsible applicant and co-applicants

Employees

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)

Abstract

The caspase-like protease MALT1 (also known as paracaspase) plays an essential role in immunity and oncogenesis in mammals. Humans and mice with mutations in the MALT1 gene show signs of severe immunodeficiency, often combined with autoimmunity, while hyperactivity of MALT1 is associated with cancers of both, hematopoietic and non-hematopoietic origin. Over the last years, we and others have intensively studied the molecular function of MALT1 underlying these pathologies. This has led to the concept that MALT1 promotes immune responses and oncogenesis mainly through the activation of the transcription factor NF-kB, which upregulates the expression of genes required for cellular proliferation and survival. Recent studies (including our own published and unpublished work) suggest that MALT1 exerts additional, NF-kB-independent functions that remain less well understood. Further support for the existence of NF-kB-independent functions of MALT1 comes from the observation that the MALT1 gene is highly conserved from mammals to simple metazoans devoid of NF-kB homologs, such as the nematode C. elegans. Here, we propose to identify novel, NF-kB-independent functions of MALT1 by two lines of investigations that will be performed using the mammalian system (humans/mice) and using C. elegans, a model organism that has given rise to fundamental paradigms in biology. The goals of this proposal are (1) to investigate the role of a newly identified, B-cell specific MALT1 substrate unrelated to NF-kB, by analyzing the functional consequences of the cleavage of this substrate for the human and mouse immune response, and (2) to identify evolutionarily conserved functions of MALT1 in the nematode C. elegans, an organism that has no evident NF-kB homologue, by combining biochemical and genetic approaches.We expect that the elucidation of these NF-kB-independent functions of MALT1 will reveal novel facets of its role in immunity and oncogenesis, which are highly relevant in view of the recent development of therapeutic MALT1 inhibitors with immunomodulatory and anti-cancer properties.
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