Les systèmes de communication cellulaire et leur régulation/ Cellular communication systems and their regulation

Séminaire organisé par Anne Spang du 11 au 16 octobre 2021

 

Participants

Francis Barr (University of Oxford, UK), Francesca Bottanelli (Freie Universitaet Berlin, Germany), Jeremy Carlton (King’s College and the Francis Crick Institute, London, UK), Pete Cullen (School of Biochemistry, Bristol, UK), Robert Ernst (Université Saarlandos, Hambourg, Germany), Ben Glick (University of Chicago), Elina Ikonen (University of Helsinki, Faculty of Medicine), Ilya Levental (University of Virginia, USA), Ian Macara (Vanderbilt University School of Medicine, Nashville, USA), Jodi Nunnari (University of California, Davis, USA), Franck Perez (CNRS, Institut Curie, Paris, France), Blanche Schwappach, Maya Schuldiner (Weizmann Institute of Science, Rehovot, Israel), Anne Spang (Biozentrum, University of Basel, Switzerland), Christian Ungermann (Osnabrück University, Innsbruck, Germany), Marino Zerial (MPI-CBG, Dresden, Germany).

 

Résumé

Ruche photographiée dans les environs des Treilles, ressemblant à l’appareil de Golgi, organelle dont il a été beaucoup question lors du séminaire.

Le séminaire « Les systèmes de communication cellulaire et leur régulation » s’est déroulé à la Fondation des Treilles en octobre 2021. Ce séminaire a réuni une quinzaine de scientifiques (40 % de femmes, deux chefs d’équipe juniors) de France, d’Europe, d’Israël et des États-Unis dans les domaines de la biologie cellulaire, de la biophysique et de la biochimie.  Les participants ont présenté leurs derniers résultats invitant à de longues discussions et à forgeant des collaborations. Plusieurs sessions étaient dédiées à des questions plus globales, portant sur l’avenir de ce domaine passionnant, sur le partage de données, sur le futur des publications scientifiques dans le 21ème siècle et sur l’intégrité de la recherche.

Les cellules de notre corps communiquent entre elles. Pour ce faire, elles doivent être capables d’émettre et de recevoir des signaux et d’interagir avec l’environnement pour adhérer ou migrer par exemple. Ces signaux sont produits à l’intérieur de la cellule et doivent être délivrés, et reçus, à la membrane plasmique. Souvent, la réception de signaux déclenche des processus qui provoquent l’élimination des protéines de la membrane plasmique. De plus, les organelles cellulaires doivent conserver leur identité, réguler le nombre de copies, la taille et l’homéostasie. La façon dont les protéines, l’ARN et les lipides sont transportés et adressés dans les cellules est l’une des questions les plus fondamentales en biologie, car un trafic et une localisation approprié des protéines et des lipides sont essentiels à la plupart des processus cellulaires. L’importance du trafic intracellulaire a déjà été reconnue par trois prix Nobel l’un en 1974 (Palade, Claude, deDuve), un en 1999 (Blobel) et un en 2013 (Schekman, Rothman, Südhof). Malgré ces reconnaissances, nous manquons encore de compréhension mécanistique des aspects clés du transport intracellulaire. Même si la plupart des acteurs moléculaires ont été identifiés, nous n’avons pas encore une connaissance fine de la régulation des voies de trafic dans différents tissus, ou le rôle de ces voies dans le développement de certaines maladies ou au cours du vieillissement. Les analyses sont compliquées par la robustesse et la redondance des mécanismes de transport. En raison de son rôle central, il existe des voies alternatives qui peuvent être régulées à la hausse en cas de blocage du trafic. De plus, nous commençons seulement à comprendre comment les composants sont réaffectés pour réguler différentes fonctions cellulaires et comment ils contribuent à l’intégration de différents systèmes de communication intracellulaire protéique et lipidique. Par conséquent, notre domaine, ancien et central, fait face à une pléthore de questions ouvertes qui sont essentielles à la compréhension fondamentale du fonctionnement d’une cellule et de ses nombreuses fonctions. Ces questions peuvent aujourd’hui être posées de façon nouvelle grâce aux nombreuses révolutions technologiques liées par exemple à l’imagerie des cellules, à l’analyse structurales ou à la génétique cellulaire. Ce séminaire a réuni des chercheurs éminents de différents domaines concernant la communication intracellulaire à travers des systèmes membranaires pour discuter ces questions et l’avenir du trafic et de la dynamique membranaires.

 

Summary

The seminar « Cellular communication systems and their regulation » took place at the Fondation des Treilles in October 2021. This meeting brought together fifteen scientist (40% female participation, two junior PIs) from France, Europe, Israel and the US from the fields of cell biology, biophysics and biochemistry. The participants presented their latest results, inviting extended discussions and forging collaborations. Moreover, fruitful discussions about key issues and about the future of this exciting field as well as publishing, data sharing and research integrity were conducted.

Cells in our body communicate with each other. In order to do so they need to be able to send off and to receive signals. These signals are provided from within the cell and need to be delivered to the plasma membrane. Likewise receiving signals triggers processes that causes the removal of proteins from the plasma membrane. Moreover, cellular organelles need to maintain their identity, regulate copy number, size and homeostasis. How proteins, RNA and lipids are transported within cells is one of the most fundamental questions in biology as proper trafficking of material is a prerequisite for most cellular processes. Even though most molecular players have been identified, we still lack understanding of the regulation of trafficking pathways in different tissues, in health and disease and during aging. The analyses are complicated by the robustness of the transport system. Because of its pivotal role, alternative pathways exist that can be upregulated if there is a traffic block. Moreover, we are still scratching at the surface to understand the repurposing of components for different cellular functions and the integration of different protein and lipid intracellular communication systems. Therefore, we have to deal with a plethora of open questions that are essential for the fundamental understanding of how a cell functions, and performs its many critical tasks. Novel tools and approaches brought for example by next generation imaging, structural analysis or genome editing allows to revisit and explore these questions. This meeting brought together prominent scientists from different domains addressing intracellular communication through membrane systems to discuss these issues and the future of research in membrane traffic and dynamics. 

 

Report

Francis Barr discussed how the KDEL receptor drives export and directionality of cargo transport in the ER-Golgi shuttle and how the affinity for a particular retrieval signal in client proteins correlates with their abundance in the endoplasmic reticulum.

Ben Glick discussed his novel data on Golgi maturation in the yeast S. cerevisiae. He showed data consistent with more than one intra-Golgi recycling pathway. Moreover, he discussed the identity of the trans-Golgi network and recycling endosomes, which appear to be collapsed into one compartment in S. cerevisiae.

Francesca Bottanelli presented her super-resolution microscopy data on the ER-Golgi intermediate compartment (ERGIC) and its relationship with the Golgi apparatus. She also discussed that the ERGIC may contain distinct domains that can be separated by the presence of small GTPases of the Arf family.

Franck Perez presented new functionalities to the RUSH system that he developed. Now one can not only observe cargo transport through the Golgi in a synchronized manner, but also endocytosis and retrograde transport to the ER. Moreover, he discussed ways for repeated waves of trafficking event and the use of protags and d-tags tags, and how to use trafficking control to develop novel therapeutic approaches.

Blanche Schwappach discussed the function of different components of the guided entry of tail-anchored proteins (GET) pathway, which facilitates integration of a subset of transmembrane containing proteins into the ER, and also described a novel client protein for this pathway.

Robert Ernst provided interesting insights into how different membrane arrangements are sensed in cells and how lipid bilayer stress is recognized by the IRE1, which is also one of the sensors of the unfolded proteins in the ER, begging the question what IRE1 is picking up: unfolded protein, bilayer stress or both?

Ilya Levental explored how a single transmembrane may guide the localization of a protein. Surprisingly, the exchange of three hydrophobic residues to three other hydrophobic amino acids shifted the protein from the plasma membrane to an internal compartment. The bulkiness of the transmembrane domains may determine their partitioning into more ordered or more disordered lipid membrane domains in giant plasma membrane vesicles.

Elina Ikonen discussed an exciting model on the communication between lipid droplets (LDs) and the ER in which the LDs form a continuum with the ER and the transport of triglycerides is facilitated by seipin. Moreover, seipin plays an important role not only in LD biogenesis but also in securing the growth of small LDs by inhibiting ripening.

Ian Macara provided striking insights on the assembly and function of the exocyst tethering complex. The functional and quantitative analysis revealed that exocyst may have to disassemble before vesicle fusion with the plasma membrane could occur.

Jodi Nunnari highlighted the importance of mitochondrial dynamics and how this directly connected to the metabolic state of the cell. She reported on a mitochondrial solute transporter important for mitochondrial fusion in response to starvation, via a mechanism involving lyso-phosphatidic acid.

Maya Schuldiner reminded all of the importance of organellar contact sites, which she has systematically mapped in S. cerevisiae. The first identified component of the nuclear-mitochondrial contact acts as a tether for these organelles, the concentration of which on the nucleus is regulated by phosphatidylcholine abundance.

Jeremy Carlton (EMBO Young Investigator Lecture) explained his novel data on ESCRT-III involvement in nuclear envelope reformation in M-phase exit. Spatiotemporally controlled phosphorylation and dephosphorylation of ESCRT-III by CDK1 licenses its assembly at the nuclear envelope but prevents assembly on the endoplasmic reticulum at the same time to allow nuclear envelope regeneration.  

Pete Cullen (via Zoom) discussed the different sorting nexin-dependent recycling pathways in the endosomal system to the plasma membrane and the Golgi apparatus. Intriguingly, the subunit composition of the ESCPE-1 complex appeared to determine whether ESCPE-1 supports recycling to the plasma membrane or the Golgi apparatus.

Christian Ungermann reported on great progress in the biochemical reconstitution of steps in endosome maturation, namely Rab conversion and HOPS recruitment. Importantly, the recruitment of the Rab7GEF to the membrane can occur independently of Rab5. However, Rab7GEF activity requires the presence of Rab5, presumably through a mechanism that relieves Rab7GEF inhibition. This then allows for Rab7 recruitment and activation, and subsequent HOPS recruitment.

Anne Spang discussed first their current model on Arf1 acts on mitochondrial dynamics and function. Then she provided evidence for kiss-and-run of early endocytic structures and recycling endosomes with sorting endosomes as a means to potentially increase robustness and fidelity in sorting processes.

Marino Zerial emphasized the role of mechanics in membrane structure and function. On early endosomes, he explained that the tether EEA1 and Rab5 constitute a two-component motor performing mechanical work in membrane tethering to fusion.  He then moved on to discuss his work on the polarization of hepatocytes, where apical membrane connections determine the anisotropic expansion of bile canaliculi during liver tissue morphogenesis.  

In the evenings, the group discussed issues of more general importance. There was a discussion on the future of membrane traffic and dynamics (chaired by Marino Zerial), and two EMBO Science Policy Lectures and Discussions on Open Access and Publishing in the 21st century (Jodi Nunnari) and on Research Integrity (Ian Macara). All discussion were very lively and thought-provoking, and went well beyond the allotted times. Dissemination of some of the ideas that surfaced at the discussions with stakeholders was envisaged and encouraged.

The beautiful location of Les Treilles, the outstanding support by all the staff at the Fondation des Treilles and the amazing scientific atmosphere were very much appreciated by all the participants. The participants were also grateful for the astronomy night excursion.


Rechercher dans OpenEdition Search

Vous allez être redirigé vers OpenEdition Search