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

English title S-palmitoylation: from anthrax toxin receptors to the human palmitome
Applicant van der Goot Gisou
Number 156898
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 01.01.2015 - 31.12.2017
Approved amount 1'025'595.00
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Keywords (5)

signaling; anthrax toxin; Hyaline fibromatosis syndrome; protein palmitoylation; calnexin

Lay Summary (French)

Lead
Etude sur la modification chimique des protéines pour changer leur fonction ainsi que des mécanismes d'une maladie génétique, le syndrome de la fibromatose hyaline
Lay summary

Le génome humain encode ≈20’000 gènes. Ces gènes contiennent la “recette” pour fabriquer des protéines. Une cellule et encore plus un organisme multicellulaire comme l’homme, utilise bien plus de 20’000 protéines pour fonctionner de manière optimale. Les cellules ont donc évolué des mécanismes complexes pour amplifier la diversité des protéines. Une des méthodes est de modifier chimiquement, et de manière réversible, les protéines afin de leurs conférer des propriétés différentes. Ces modifications s’appellent des « modifications post-traductionnelles ». Notre laboratoire s’intéresse à une modification très particulière, essentielle pour l’organisme mais peu comprise et qui consiste à rajouter sur une protéine un long acide gras saturé.  Cette modification se nomme S-palmitoylation. Nous étudierons dans ce projet les enzymes qui permettent cette modification ainsi que les enzymes qui la réversent. Nous étudierons la dynamique de la modification et ses conséquences physiologiques.

Notre intérêt pour cette modification a été suscité par nos études sur une protéine appelé CMG2. CMG2 est la protéine qui permet à la toxine produite par la bactérie anthrax de rentrer dans nos cellules et induire la mort. Mais ceci est une utilisation opportuniste par la bactérie. Le role normal de CMG2 n’est pas connu. Nous savons par contre que des mutations génétiques chez l’humain entrainent une maladie très grave et souvent mortelle: le syndrome de la  fibromatose hyaline . Nous poursuivrons donc aussi au sein de ce projet nos études visant à comprendre le rôle physiologique de CMG2 et comment la perte de fonction de cette protéine entraine une maladie aussi handicapante.

Direct link to Lay Summary Last update: 15.01.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes.
Kathayat RS Cao Y Elvira PD Sandoz PA Zaballa ME Springer MZ Drake LE Macleod KF van der Goo (2018), Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes., in Nature Communications, 334.
Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade
Abrami Laurence, Dallavilla Tiziano, Sandoz Patrick A, Demir Mustafa, Kunz Béatrice, Savoglidis Georgios, Hatzimanikatis Vassily, van der Goot F Gisou (2017), Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade, in eLife, 6, 1-24.
CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome
Bürgi Jérôme, Kunz Béatrice, Abrami Laurence, Deuquet Julie, Piersigilli Alessandra, Scholl-Bürgi Sabine, Lausch Ekkehart, Unger Sheila, Superti-Furga Andrea, Bonaldo Paolo, van der Goot F. Gisou (2017), CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome, in Nature Communications, 8, 15861-15861.
The Ins and Outs of Anthrax Toxin
Friebe Sarah, van der Goot F., Bürgi Jérôme (2016), The Ins and Outs of Anthrax Toxin, in Toxins, 8(12), 69-69.
Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6
Perrody Elsa, Abrami Laurence, Feldman Michal, Kunz Beatrice, Urbé Sylvie, van der Goot F Gisou (2016), Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6, in eLife, 5, 1-14.
Intrinsic Disorder in Transmembrane Proteins: Roles in Signaling and Topology Prediction
Bürgi Jérôme, Xue Bin, Uversky Vladimir N., van der Goot F. Gisou (2016), Intrinsic Disorder in Transmembrane Proteins: Roles in Signaling and Topology Prediction, in PLOS ONE, 11(7), e0158594-e0158594.
Revealing Assembly of a Pore-Forming Complex Using Single-Cell Kinetic Analysis and Modeling
Bischofberger Mirko, Iacovache Ioan, Boss Daniel, Naef Felix, van der Goot F. Gisou, Molina Nacho (2016), Revealing Assembly of a Pore-Forming Complex Using Single-Cell Kinetic Analysis and Modeling, in Biophysical Journal, 110(7), 1574-1581.
Model-Driven Understanding of Palmitoylation Dynamics: Regulated Acylation of the Endoplasmic Reticulum Chaperone Calnexin
Dallavilla Tiziano, Abrami Laurence, Sandoz Patrick A., Savoglidis Georgios, Hatzimanikatis Vassily, van der Goot F. Gisou (2016), Model-Driven Understanding of Palmitoylation Dynamics: Regulated Acylation of the Endoplasmic Reticulum Chaperone Calnexin, in PLOS Computational Biology, 12(2), e1004774-e1004774.
Pore-forming toxins: ancient, but never really out of fashion
Peraro Matteo Dal, van der Goot F. Gisou (2016), Pore-forming toxins: ancient, but never really out of fashion, in Nature Reviews Microbiology, 14(2), 77-92.
SwissPalm: Protein Palmitoylation database
Blanc Mathieu, David Fabrice, Abrami Laurence, Migliozzi Daniel, Armand Florence, Bürgi Jérôme, van der Goot Françoise Gisou (2015), SwissPalm: Protein Palmitoylation database, in F1000Research, 1-23.
Differential Dependence on N-Glycosylation of Anthrax Toxin Receptors CMG2 and TEM8
Friebe Sarah, Deuquet Julie, van der Goot F. Gisou (2015), Differential Dependence on N-Glycosylation of Anthrax Toxin Receptors CMG2 and TEM8, in PLOS ONE, 10(3), e0119864-e0119864.

Collaboration

Group / person Country
Types of collaboration
Prisca Liberali, FMI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Vassily Hatzimanikatis, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Matteo Dal Peraro, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Nicolas Demaurex, UNIGE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Tatiana Petrova, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Andrea Superti-Furga/CHUV Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ekkehart Lausch /Uni Klinik Freiburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
John Martignetti / Mount Sinai United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Marcos Gonzalez Gaitan/ UNIGE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
176393 Bonus of Excellence -S-palmitoylation: from anthrax toxin receptors to the human palmitome 01.01.2018 Project funding (Div. I-III)

Abstract

Surface receptors are major mediators of the communication between a cell and its environment. Given their ability to signal and/or be internalized, they have often been high jacked by pathogenic organisms. My laboratory has had a long-term interest in host-pathogen interactions. We have in particular dissected the unusual and highly efficient entry route of the anthrax toxin. The toxin can interact with either one of two receptors, which to a large extent drive the path followed by the toxin. We have become increasingly interested in these receptors, the physiological roles of which are still poorly understood. Our work has revealed that the receptors are subject to multiple post-translational modifications, including phosphorylation, ubiquitination and S-palmitoylation. This later modification consists in the addition of an acyl chain to cysteines and is the only lipid modification that is reversible, thus conferring to this acylation the capacity to act as a switch for protein function. Despite its increasingly acknowledged importance, very little is known about this versatile modification. Over the last years, we have therefore broadened our research scope to study S-palmitoylation beyond the anthrax toxin receptor, at the organellar and cellular levels. During the upcoming granting period, we plan to pursue both the anthrax toxin receptor and palmitoylation lines of research.A. Physiological and pathological roles of the anthrax toxin receptorsAnthrax toxin has two receptors, Capillary Morphogenesis gene 2 (CMG2) and Tumor endothelial marker 8 (TEM8). Mutations in the genes encoding these receptors lead to two severe, apparently unrelated, genetic diseases, Hyaline Fibromatosis Syndrome for CMG2 and GAPO syndrome for TEM8. While they are most likely involved in homeostasis of the extracellular matrix, little is known about the molecular function of these plasma membrane proteins. With a major focus on CMG2, we will:1.Perform an in depth mechanistic analysis of the receptor-driven anthrax toxin intoxication routes2.Analyze CMG2-mediated signaling across the plasma membrane3.Determine the consequences of CMG2 loss-of-function and their relationship to the phenotypes observed in HFS patients (mainly deregulation of the extracellular matrix)B. S-Palmitoylation, its roles and regulationThe list of proteins that undergo palmitoylation is ever increasing, including key cellular proteins involved in adhesion, signaling, protein folding or gene expression. In the cytosol, this modification is mediated by enzymes of the DHHC family, of which there are 23 in humans, and reversed by acyl protein thioesterases (APTs) of which 3 have so far been identified. Extremely little is known about either of these classes of enzymes. We will therefore analyze both palmitoylation and depalmitoylation, focusing on a few specific DHHC enzymes, the APTs and a selected set of substrates. The overall aims are to understand the dynamics of palmitoylation-depalmitoylation and how they are regulated, and the importance of S-palmitoylation in controlling the formation of protein platforms, in particular at site of contact between organelles. More specifically we will:1.Evaluate the importance of APTs and how their activity is regulated by palmitoylation, phosphorylation and ubiquitination.2.Analyze the distribution, function and regulation of DHHCs at the cellular and organismal levels.3.Analyze the roles of S-palmitoylation in the formation and function of inter-organellar synapses.
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