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Bonus of Excellence -S-palmitoylation: from anthrax toxin receptors to the human palmitome

English title Bonus of Excellence - S-palmitoylation: from anthrax toxin receptors to the human palmitome
Applicant van der Goot Gisou
Number 176393
Funding scheme Project funding (Div. I-III)
Research institution Global Health Institute EPFL SV-DO
Institution of higher education EPF Lausanne - EPFL
Main discipline Cellular Biology, Cytology
Start/End 01.01.2018 - 31.12.2020
Approved amount 1'006'190.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Biochemistry

Keywords (6)

anthrax; DHHC; palmitoylation; CMG2; Acyl Protein thioesterase; collagen VI

Lay Summary (French)

Lead
Notre génome contient l’information pour générer quelques 20'000 protéines. Celles-ci peuvent ensuite être modifiées par des enzymes, pour obtenir une régulation plus fine, dans le temps et dans l’espace, de leur activité. Chaque individu a un génome qui lui est propre, ceci engendre une partie de la diversité humaine. Certaines des variations dans le génome peuvent être délétères et engendrer des maladies dites génétiques. Le projet porte sur un gène particulier, pour lequel certaines variations entrainent un syndrome rare mais très sévère.
Lay summary

Le nom de notre gène est cmg2, celui de la protéine, CMG2. Si cette protéine ne fonctionne pas à cause d’une variation dans le gène, l’enfant meurt avant l’âge de 2 ans. Mais ironiquement, nous connaissons mal la fonction de la protéine CMG2. Dans ce projet nous nous focaliserons sur trois rôles potentiels: 1) dans la communication entre la cellule et son environnement ; 2) dans la formation du tissue adipeux, c.-à-d. la graisse de notre corps ; 3) dans la régénération musculaire, en particulier après une blessure. Nos pistes préliminaires indiquent effectivement que CMG2 pourrait jouer un rôle dans ces processus.

Pour fonctionner, CMG2 subit de plus une modification enzymatique: l’ajout d’un lipide. Nous analyserons aussi les conséquences de cette modification et comment elle est régulée.

 

Ce projet se situe à l’interface entre la recherche fondamentale et la recherche appliquée. Son but est de mieux comprendre le rôle d’une protéine spécifique dans le développement et fonctionnement des mammifères, ainsi que les conséquences de son dysfonctionnement menant à une maladie rare. Le projet aussi à mieux comprendre comment la fonction des protéines peut être modifié par des modifications chimiques.

Direct link to Lay Summary Last update: 08.01.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains
Abrami Laurence, Audagnotto Martina, Ho Sylvia, Marcaida Maria Jose, Mesquita Francisco S., Anwar Muhammad U., Sandoz Patrick A., Fonti Giulia, Pojer Florence, Dal Peraro Matteo, van der Goot F. Gisou (2021), Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains, in Nature Chemical Biology, 17(4), 438-447.
Harnessing the Membrane Translocation Properties of AB Toxins for Therapeutic Applications
PiotNuma, van der GootGisou F, SergeevaOksana A (2021), Harnessing the Membrane Translocation Properties of AB Toxins for Therapeutic Applications, in Toxins (Basel), 36.
Wnt-controlled sphingolipids modulate Anthrax Toxin Receptor palmitoylation to regulate oriented mitosis in zebrafish
CastanonIrinka, HannichJ Thomas, AbramiLaurence, HuberFlorian, DuboisM, MullerM, van der GootGisou F, Gonzalez-GaitanMarcos (2020), Wnt-controlled sphingolipids modulate Anthrax Toxin Receptor palmitoylation to regulate oriented mitosis in zebrafish, in Nature Communications, 3317.
Ligand Binding to the Collagen VI Receptor Triggers a Talin-to-RhoA Switch that Regulates Receptor Endocytosis
BürgiJérôme, AbramiLaurence, CastanonIrinka, AbriataLuciano A, KunzBéatrice, YanShixu Emili, LeraManuel, UngerSheila, Superti-FurgaAndrea, Dal PeraroMatteo, Gonzalez GaitanMarcos, van der GootGisou F (2020), Ligand Binding to the Collagen VI Receptor Triggers a Talin-to-RhoA Switch that Regulates Receptor Endocytosis, in Developmental Cell, 418.
Mammalian membrane trafficking as seen through the lens of bacterial toxins
Sarmento MesquitaFrancisco, van der GootGisou F, SergeevaOksana A (2020), Mammalian membrane trafficking as seen through the lens of bacterial toxins, in Cellular Microbiology, 22.
Hemagglutinin of Influenza A, but not of Influenza B and C viruses is acylated by ZDHHC2, 8, 15 and 20
GadallaMohamed Rasheed, AbramiLaurence, van der GootGisou F, VeitMichael (2020), Hemagglutinin of Influenza A, but not of Influenza B and C viruses is acylated by ZDHHC2, 8, 15 and 20, in Biochem J, 285.
Image-based analysis of living mammalian cells using label-free 3D refractive index maps reveals new organelle dynamics and dry mass flux
SandozPatrick A, TremblayChristopher, van der GootGisou F, FrechinMathieu (2019), Image-based analysis of living mammalian cells using label-free 3D refractive index maps reveals new organelle dynamics and dry mass flux, in PLoS Biol, 17.
Converging physiological roles of the anthrax toxin receptors
SergeevaOksana A, van der GootGisou F (2019), Converging physiological roles of the anthrax toxin receptors, in F1000Research, 8.
Dynamic Radiolabeling of S-Palmitoylated Proteins
AbramiLaurence, Denhardt-ErikssonRobin A, HatzimanikatisVassily, van der GootGisou F (2019), Dynamic Radiolabeling of S-Palmitoylated Proteins, in Linder Maurine E (ed.), Humana, New York, 111.
SwissPalm 2: Protein S-Palmitoylation Database
BlancMathieu, DavidFabrice PA, van der GootGisou F (2019), SwissPalm 2: Protein S-Palmitoylation Database, in Linder Maurine E (ed.), Humana, New York, 203.
Aerolysin, a Powerful Protein Sensor for Fundamental Studies and Development of Upcoming Applications
CressiotBenjamin, OuldaliHadjer, Pastoriza-GallegoManuela, BacriLaurent, van der GootGisou F, PeltaJuan (2019), Aerolysin, a Powerful Protein Sensor for Fundamental Studies and Development of Upcoming Applications, in ACS Sensors, 530.
Anthrax toxin requires ZDHHC5-mediated palmitoylation of its surface-processing host enzymes
SergeevaOksana A, van der GootGisou F (2019), Anthrax toxin requires ZDHHC5-mediated palmitoylation of its surface-processing host enzymes, in Anthrax toxin requires ZDHHC5-mediated palmitoylation of its surface-processing host enzymes , 1279.
Palmitoylation mediates membrane association of hepatitis E virus ORF3 protein and is required for infectious particle secretion
GouttenoireJérôme, Pollán Angela, AbramiLaurence, Oechslin Noémie, MauronJohann, MatterMaxime, OppligerJoël, Szkolnicka Dagmara, Dao ThiViet Loan, van der GootGisou F, MoradpourDarius (2018), Palmitoylation mediates membrane association of hepatitis E virus ORF3 protein and is required for infectious particle secretion, in PLoS Pathogens, 14.
The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics
ZaballaMaria Eugenia, van der GootGisou F (2018), The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics, in Crit Rev Biochem Mol Biol, 53.
Targeting STING with covalent small-molecule inhibitors
HaagSimone M, GulenMuhammet F, ReymondLuc, GibelinAntoine, AbramiLaurence, DecoutAlexiane, HeymannMichael, van der GootGisou F, TurcattiGerardo, Behrendt Rayk, AblasserAndrea (2018), Targeting STING with covalent small-molecule inhibitors, in Nature, 269.
Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes
Kathayat Rahul S, CaoYang, ElviraPablo D, SandozPatrick A, ZaballaMaria-Eugenia, SpringerMaya Z, DrakeLauren E, MacleodKay F, van der GootGisou F, DickinsonBryan C (2018), Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes, in Nature Communications, 334.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Cell Bio Virtual 2020, ASCB/EMBO conference Poster Physiological role of CMG2 in intestinal lymphatic development 02.12.2020 online, United States of America Bracq Lucie;
internal seminar via videoconference, Cochin Institute Individual talk Dynamics of protein palmitolation, focus on the anthrax toxin receptor 08.10.2020 Paris, France van der Goot Gisou;
Joint LV Annual SAIB Meeting and XIV PABMB conference Talk given at a conference EMBO Keynote lecture: DYNAMIC CONTROL OF PROTEIN FUNCTION BY PALMITOYLATION 05.11.2019 Salta, Argentina van der Goot Gisou;
Endoplasmic Reticulum meeting 2019 : Endoplasmic Reticulum, from basic cell biology to translational approaches: a path to the clinic Talk given at a conference Dynamic palmitoylation as a means to regulate ER structure and function 09.10.2019 Paris, France van der Goot Gisou;
FASEB "The Protein Lipidation Conference: Enzymology, Signaling and Therapeutics" Talk given at a conference Molecular mechanism of human acyl-protein thioesterase 2 catalyzed depalmitoylation 07.07.2019 Olean, New York, United States of America van der Goot Gisou;
EMBO Workshop - Protein quality control: From mechanisms to disease Poster posters presented by Laurence Abrami (paid by EPFL), G. Brambilla and F. Mesquita 28.04.2019 Costa de la Calma (Mallorca), Spain Mesquita Francisco; Brambilla Pisoni Giorgia;
IMPRS-CMB Students Retreat Individual talk Controlling protein function by lipid modification reversible lipid attachment 04.04.2019 Maria in der Aue, near Köln, Germany van der Goot Gisou;
2019 Membrane Biophysics of Exo-Endocytosis meeting Poster not known 03.04.2019 Mandelieu-la-Napoule, France Piot Numa;
Keystone symposium: Phenotypic Drug Discovery: Recent Advances and Insights from Chemical and Systems Biology (C1) Poster poster, title not known 03.03.2019 Breckenridge, CO, United States of America Sergeeva Oksana;
seminar co-hosted by the Cell and Developmental and the Immunology and Pathogenesis divisions, UCB Individual talk Protein palmitoylation in health and disease: from Wnt signaling to anthrax 04.12.2018 Berkeley, United States of America van der Goot Gisou;
17th workshop "Cell Biology of Viral Infections", German Society for Virology Individual talk keynote lecture. title not kept 16.10.2018 Schöntal, Germany van der Goot Gisou;
Acylation of intracellular and secreted proteins: mechanisms and functional outcomes Talk given at a conference Talk given by Laurence Abrami (paid by EPFL), poster contributions by O. Sergeeva and G. Brambilla 10.09.2018 Brighton, Great Britain and Northern Ireland Sergeeva Oksana; Brambilla Pisoni Giorgia;
Internal seminar at the Broad Institute Individual talk not kept. On CGM2 and TEM8 06.03.2018 Boston, United States of America van der Goot Gisou;


Awards

Title Year
SUFFRAGE SCIENCE AWARDS Life Sciences Awardee 2020 https://www.suffragescience.org/post/gisou-van-der-goot 2020

Associated projects

Number Title Start Funding scheme
156898 S-palmitoylation: from anthrax toxin receptors to the human palmitome 01.01.2015 Project funding (Div. I-III)

Abstract

During the upcoming granting period, we will pursue the two research axes of the 2014 proposal, namely 1) study of the physiological and pathological roles of anthrax toxin receptors, and 2) seek a better understanding of S-palmitoylation in the context of anthrax toxin receptors but also more generally.Anthrax toxin receptors. We will finalize and validate our screens on exosome biogenesis and uptake using anthrax toxin as a tool (not further described here) and pursue our studies on the molecular requirements of anthrax toxin signaling and trafficking. We will also launch a new research avenue that builds on our recent finding that the anthrax toxin receptor, CMG2, is a receptor for Collagen VI. We will investigate the role of CMG2 in fat metabolism and in muscle regeneration, since collagen VI has been shown to play an important role in these processes.S-palmitoylation. CMG2 undergoes palmitoylation. Preliminary experiments indicate that this is important for CMG2 folding in the endoplasmic reticulum, residence time at the cell surface and signaling capacity. We will investigate these processes in detail, study the dynamics of palmitoylation-depalmitoylation and examine how these processes are regulated. To do so, as successfully done in the past, we will combine a vast panel of approaches including in vitro structural and enzymatic analyses, cell-based functional and morphological assays, animal experimentation and mathematical modeling.
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