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Molecular mechanisms linking ER-stress and inflammatory pathways

Applicant Martinon Fabio
Number 130476
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 01.08.2010 - 31.07.2014
Approved amount 331'000.00
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All Disciplines (4)

Discipline
Biochemistry
Immunology, Immunopathology
Molecular Biology
Cellular Biology, Cytology

Keywords (7)

er-stress; inflammation; type I interferon; kinases; Endoplasmic reticulum; unfolded protein response; signaling

Lay Summary (French)

Lead
Lay summary
Le réticulum endoplasmique est une organelle essentielle au bon fonctionnement de chacune des cellules eucaryotes. Ce projet étudie comment cette organelle peut détecter des perturbations cellulaires pour réguler la réponse inflammatoire. Résumé :Le réticulum endoplasmique remplit plusieurs fonctions, il facilite l'assemblage de protéines en unités fonctionnelles, il permet le transport de protéines localisées dans les membranes de la cellule ou secrétées dans le milieu extracellulaire. Le réticulum endoplasmique joue aussi un rôle important dans la détection de perturbations cellulaires qui peuvent affecter son bon fonctionnement. Suite au stress dans le réticulum endoplasmique, des senseurs sont activés déclenchant une cascade d'évènements moléculaire qui résulte dans la synthèse de nouvelles protéines réparatrices. Cette réponse est essentielle à la survie et au développement de nombreux types de cellules. De récentes observations suggèrent que l'activation des senseurs du stress dans le réticulum endoplasmique peut contribuer au développement d'une réaction inflammatoire. Le rôle de cette réaction inflammatoire et les mécanismes moléculaires qui la caractérisent sont encore peu connus. But : Ce projet a dans un premier temps comme objectif d'élucider les mécanismes moléculaires qui permettent aux senseurs du stress dans le réticulum endoplasmique de réguler la réponse inflammatoire. Le projet vise dans un deuxième temps à comprendre quelle est la relevance physiologique de l'inflammation activée par le stress dans le réticulum endoplasmique. Signifiance : Ce projet permet de mieux comprendre comment une perturbation ou un stress au niveau cellulaire peuvent réguler une réponse, l'inflammation, qui va affecter l'organisme dans sont entier. De nombreuses maladies sont caractérisées par la présence de signes qui suggère un stress dans le réticulum endoplasmique. C'est le cas par exemple de la mucoviscidose, de la maladie de gaucher et de certaines maladies neurodégéneratives comme la maladie d'Alzheimer qui produisent des protéines incapables d'être assemblées correctement ou formant des agrégats menant à une perturbation dans le réticulum endoplasmique. Ces maladies ont une composante inflammatoire. Ce projet mènera probablement à la découverte d'indices sur un rôle de la réponse au stress cellulaire dans le développement de pathologies inflammatoires caractérisées par une perturbation du réticulum endoplasmique
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Crystal structure of NLRC4 reveals its autoinhibition mechanism.
Hu Zehan, Yan Chuangye, Liu Peiyuan, Huang Zhiwei, Ma Rui, Zhang Chenlu, Wang Ruiyong, Zhang Yueteng, Martinon Fabio, Miao Di, Deng Haiteng, Wang Jiawei, Chang Junbiao, Chai Jijie (2013), Crystal structure of NLRC4 reveals its autoinhibition mechanism., in Science (New York, N.Y.), 341(6142), 172-5.
Did cholera toxin finally get caught?
Martinon Fabio, van der Goot F Gisou (2013), Did cholera toxin finally get caught?, in Cell host & microbe, 13(5), 501-3.
Dangerous Liaisons: Mitochondrial DNA Meets the NLRP3 Inflammasome
Martinon F (2012), Dangerous Liaisons: Mitochondrial DNA Meets the NLRP3 Inflammasome, in IMMUNITY, 36(3), 313-315.
The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses.
Martinon Fabio (2012), The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses., in Microbes and infection / Institut Pasteur, 14(14), 1293-300.
Editorial overview.
Glimcher Laurie H, Martinon Fabio, Modlin Robert L (2011), Editorial overview., in Current opinion in immunology, 23(1), 1-2.
Jurg Tschopp-1951-2011-an immortal contribution Obituary
Kroemer G, Martinon F, Lippens S, Green DR, Knight R, Vandenabeele P, Piacentini M, Nagata S, Borner C, Simon HU, Krammer P, Melino G (2011), Jurg Tschopp-1951-2011-an immortal contribution Obituary, 18(7), 18(7).
Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum.
Fabio Martinon and Laurie H Glimcher (2011), Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum., in Curr Opin Immunol, 23(1), 35-40.
The Inflammasomes
Virginie Pétrilli Isabelle Couillin Fabio Martinon (2011), The Inflammasomes, Birkhauser, Basel.
The unfolded protein response: integrating stress signals through the stress sensor IRE1α
Hetz C, Martinon F, Rodriguez D, Glimcher LH (2011), The unfolded protein response: integrating stress signals through the stress sensor IRE1α, in PHYSIOLOGICAL REVIEWS, 91(4), 1219-1243.
Targeting endoplasmic reticulum signaling pathways in cancer.
Martinon Fabio, Targeting endoplasmic reticulum signaling pathways in cancer., in Acta oncologica (Stockholm, Sweden).
The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses.
Martinon Fabio, The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses., in Microbes and infection / Institut Pasteur.

Collaboration

Group / person Country
Types of collaboration
Dr. Laurie Glimcher, Cornell University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
34th European Workshop for Rheumatology Research (EWRR) Workshop, Lisbon February 2014 Talk given at a conference News from the Inflammasome 20.02.2014 Lisbon, Portugal Martinon Fabio;
7th Congress of ISSAID, International Society of Systemic Auto-Inflammatory Diseases. Talk given at a conference Stress pathways in Inflammation 22.05.2013 Lausanne, Switzerland Martinon Fabio;
European League Against Rheumatism (EULAR) meeting 2012 Talk given at a conference Stress pathways promoting inflammation 06.06.2012 Berlin, Germany , Germany Martinon Fabio;
Annual Meeting of the French Society for Immunology (SFI 2011) Talk given at a conference Stress pathways promoting inflammation 08.11.2011 Montpellier, France, France Martinon Fabio;
ISREC Symposium 2011, Hallmarks and Horizons of Cancer Talk given at a conference Jürg Tschopp, death-domain folds and the inflammasome 07.09.2011 Lausanne Switzerland , Switzerland Martinon Fabio;
19th Euroconference on Apoptosis Metabolism, Epigenetics and Cell Death Talk given at a conference Perspectives on the inflammasome 14.06.2011 Stockholm, Sweden, Sweden Martinon Fabio;
Seminar series Leeds Institute of Molecular Medicine, St James's University Hospital Talk given at a conference Stress pathways promoting inflammation 03.06.2011 Leeds, UK, Great Britain and Northern Ireland Martinon Fabio;


Associated projects

Number Title Start Funding scheme
173152 Inflammatory pathways initiated by perturbations of cellular homeostasis 01.04.2017 Project funding (Div. I-III)
145002 Microscale thermophoresis for the Faculty of Bology and Medicine in Lausanne 01.12.2012 R'EQUIP

Abstract

The endoplasmic reticulum (ER) serves many general functions, including the facilitation of protein folding and the transport of synthesized proteins, but it also has an important role in sensing cellular stress. ER-stress identifies a group of signals that induce a transcriptional program enabling cells to survive protein overload and injury in the ER. This highly coordinated response involves three parallel signaling branches localized at the ER, namely IRE1, ATF6 and PERK. New findings suggest that these signaling pathways can initiate inflammation and, in specialized cells and tissues, may be involved in the pathogenesis of inflammatory and infectious diseases. However, this is an emerging field of research and little is known on the specific nature of these signaling pathways and their function in regulating immunity.The long term goals of this proposal are: to elucidate the molecular mechanisms and pathways emerging from the ER and regulating innate immune responses, and to address the physiological role of ER-stress in inflammation. Two complementary research sub-projects were designed to provide a comprehensive study of molecular mechanisms and to address the physiological role of ER stress in regulating immune responses. The first sub-project will investigate the molecular nature of inflammatory ER-stress responses, by focusing on the biochemical characterization of signaling pathways emerging from the ER-associated kinases IRE1 and PERK as well as on how these signals affect innate immune and inflammatory responses. The second sub-project is aimed at identifying physiologically relevant signals that may promote inflammation by causing ER-stress. The knowledge gained from this study will provide a better understanding of regulatory pathways controlling immune responses and will aid in the development of therapies aimed at improving the outcome of diseases characterized by inflammation and ER-stress.
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