Autophagie (De la caractérisation moléculaire et cellulaire aux applications en santé) / Autophagy (Moving from Molecular and Cellular characterization towards Applications in Health and Diseases)

Séminaire organisé Frank Lafont (Institut Pasteur, Lille, France) et Patrice Codogno (INEM, Paris, France) par du 18 au 23 mai 2015

Participants

Christian Behrends, Martine, Biard-Piechaczyk, Patricia Boya, Patrice Codogno, Ivan Dikic, Zvulun Elazar, Manolis Fanto, Mathias Faure, Gian Maria Fimia, Malene Hansen, Nicholas Ktistakis, Frank Lafont, Serge Mostowy, Christian Münz, Tassula Proikas-Cezanne, Emmanuelle Passegué, Fulvio Reggiori, Anne Simonsen, Sharon Toose, Isabelle Vergne

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Résumé

Autophagy has attracted a lot of interest these recent years as seen by the exponential growth of articles and citations. Autophagy has been involved in major global health issues (aging, cancer, diabetes, neurodegenerative diseases, infection, immunity/inflammation). The molecular bases of autophagosome formation have been largely unveiled. Currently a major trend is to focus on the regulation of autophagy during physiological changes (e.g., nutrition) and pathological situations. The ultrastructural phenotypical characterization of autophagosomes is also on the way. Thus, what are the next challenges in this emerging field? What is the real impact of autophagy on human health? How defining biomarkers? How can we envisage therapeutic tools? To address these issues 20 scientists (including 6 young group leaders) from different fields met at Les Treilles combining expertise on several experimental models, physiopathological examples and various leading edge technologies. It appeared the right timing for a Think Tank to address integrative approaches to define the next key challenges to be addressed in order to obtain molecular targets able to impact the autophagy signaling pathway in a clinical context.

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Compte-rendu

General aim

The aim of the meeting was first to establish the current landscape of the autophagy field portraying ongoing studies combining different experimental models (mammals, drosophila, worm, fish) and physiopathological issues (cancer, aging, neurological and metabolic diseases, infection/inflammation/immunity), and based on leading edge technologies. Second, a discussion was carried out in order to tackle the issues of (i) how different inducers impact the core machinery in different cellular context, (ii) how the core machinery works and (iii) how to define biomarkers (for diagnostic and therapeutic purposes). Finally, a discussion on application potentials and limitation for clinical diagnosis and therapy was launched.

The actors

The theme of the conference has initially emerged from discussions between participants held in meetings where it appeared obvious that, after a fast exponential growth, the field needed a reflection time nourished in a multidisciplinary perspective. Twenty scientific from Europe and overseas, seniors and juniors, met in the gorgeous site of Les Treilles from the 18th till the 23rd of May 2015. The two organizers of the meeting, Frank Lafont and Patrice Codogno insisted in creating the conditions to discuss basic issues as well as therapeutic forecast. As usual in Les Treilles, a large part was devoted to discussions even though each participant had the time to give an overview of the ongoing research sharing unpublished data.

The conference

Autophagy is a ubiquitous process required to maintain healthy cellular life cycle balance during development and for organism physiological equilibrium. The mechanisms that are at the basis of autophagy occur at different dimensions from the molecular level, to subcellular/cellular level and finally the whole body level. As time is concerned autophagy processes take place below the scale of nanoseconds (e.g. ubiquitin-mediated biochemical reactions) or within minutes (for example the degradation of organelles into autophagosome/autolysosome). Different approaches have been developed from the fate of protein degradation with incorporated radioelement to imaging approaches to bridge these spatiotemporal dimensions. The experimental models developed started from different cell types to whole organism approaches (e.g. drosophila, Caenorhabditis elegans, zebrafish, mice) with the objective to understand the role of autophagy beyond its cell autonomous function.

During the conference, experts of different autophagy activation modalities (for instance infectious models, starvation, pathological disorders (e.g. cancer), development) have portrayed their particular challenges in the study of autophagy at the different scales. These depictions were contrasted with technological developments to pave the way to decipher autophagy signaling pathways. This was done focusing on the current frontiers in molecular (including the underestimated lipid level) aspects of selective autophagy including macroautophagy and CMA before tackling issues on non-canonical autophagic pathways. Also, physiological regulations were taken up exemplified by aging, neuronal development, immunity and xenophagy. Deregulation of autophagy was illustrated by examining challenging issues on cancer, metabolic diseases and infection/inflammation/immunity. In each presentation a particular emphasis was addressed on the technological developments achieved to solve the biological question concerned.

Obtaining a comprehensive view on the complete set of modalities for autophagy involvement remains still a challenge. This requires to decipher the remaining pieces of the puzzle leading to the molecular mechanism picture underlying the signaling pathways activated. A number of presentations have highlighted the remaining issues in the molecular and cellular processes to be still focused on in the field. Among those, participants discussed the phases of induction (lectures from, I Dikic (ubiquitin-dependent triggering of autophagy), GM Fimia (Ambra), and N Ktistakis (ULK1)) and elongation with involvement of Atg proteins (lectures from S Tooze (WAC) T Proikas-Cezanne (WIPI), N Ktistakis (Atg9)) and the involvement of lipids (lectures from Z Elazar (Lipid droplets) and A Simonsen (PI)). Of course the point of the donor membrane for isolated membrane initiation has been tackled in several talks as well as the role of modulators and the regulation by post-translational modification (I Dikic, GM Fimia, N Ktistakis, S Mostowy, A Simonsen, S Tooze, I Vergne). These issues were also discussed using ultrastructural data coming from electron microscopy techniques focused on the infectious models (F Reggiori). Contribution of systemic approaches in the identification of molecular complexes thanks to high-content analysis linked to data mining was also considered for future trends (lectures from C Berhends, N Ktistakis, T Proikas-Cezanne, S Tooze). An important was also brought up on the membrane contact site involving cellular organelles (P Codogno).

The non-canonical role of ATG proteins was also a sensitive point that has been discussed in deep (lectures from C. Berhends, F. Reggiori, C. Munz).

Participants also discussed where are the conceptual gaps possibly linked to technological clefts (e.g. robust biomarkers to be used in vivo or new assays including taking benefit from organisms such as drosophila (M Fanto)) to be obtained in order to better understand the role of autophagy during development with the illustration of retinal growth (P Boya). The immunity question was debated from two viewpoints. First, the membrane trafficking leading to MHC II loading via the LC3-positive and single limiting membrane compartment (C Münz) and second using several xenophagy paradigms borrowed from virus (M Biard, M Faure, F Regiorri) and bacteria (I Dikic, F Lafont, S Mostowy, I Vergne). The role of receptors and adaptors selectivity toward cellular structures has been also the matter of intense discussions (I Dikic, S Tooze, F Lafont, A Simonsen, I Vergne, N Ktistakis, GM Fimia).

Pathological disorders were largely considered. The case of subversion of autophagy by successful invading pathogens was illustrated using bacteria as experimental system and using correlative imaging development (F Lafont). The autophagy control of ciliogenesis was discussed in the context of ciliopathies (P Codogno). Neurological disorders (P Boya) and aging are main global health problems in many countries and autophagy involvement during aging was discussed through the role of autophagy in hematopoietic stem cells differentiation (E Passegué) and non-mammalian experimental model such as C. elegans (M Hansen). From these last lectures it appears that the cross-talk between autophagy and metabolism should considered in various situations (E Passagué: Hematopoietic stem cells differentiation-M Hansen: aging). The Think Tank related to that section will concentrate on selecting molecular targets to define biomarkers to be targeted for diagnostic or therapeutic tools.

Conclusion

Unanimously the participants agreed on the very high quality of the Science presented and the exceptional quality of the discussions. A wish for a next meeting was expressed in order to establish a new point on the discovery that certainly will be obtained in this field still in its infancy. Especially for the line of therapeutic research that will be developed, confirmed and/or extended.