Etienne Morel's Lab (autophagy pathway and intracellular membrane dynamics)

About the lab

Autophagy pathway and intracellular compartments dynamics laboratory

Cell Biology Department of Institut Necker Enfants Malades
INSERM/CNRS/Université de Paris - PARIS, France

The main focus of our research team is to understand how mammalian cells' organelles and endomembranes cooperate with autophagic machinery to adapt to stressful situations and external stimuli.

Featured research (11)

Mechanical forces, such as compression, shear stress and stretching, play major roles during development, tissue homeostasis and immune processes. These forces are translated into a wide panel of biological responses, ranging from changes in cell morphology, membrane transport, metabolism, energy production and gene expression. Recent studies demonstrate the role of autophagy in the integration of these physical constraints. Here we focus on the role of autophagy in the integration of shear stress induced by blood and urine flows in the circulatory system and the kidney, respectively. Many studies highlight the involvement of the primary cilium, a microtubule-based antenna present at the surface of many cell types, in the integration of extracellular stimuli. The cross-talk between the molecular machinery of autophagy and that of the primary cilium in the context of shear stress is revealed to be an important dialog in cell biology.
The primary cilium (PC), a plasma membrane microtubule-based structure, is a sensor of extracellular chemical and mechanical stress stimuli. Upon ciliogenesis, the autophagy protein ATG16L1 and the ciliary protein IFT20 are co-transported to the PC. We demonstrated in a recent study that IFT20 and ATG16L1 interact in a multiprotein complex. This interaction is mediated by the ATG16L1 WD40 domain and an ATG16L1-binding motif newly identified in IFT20. ATG16L1-deficient cells are decorated by giant ciliary structures hallmarked by defects in PC-associated signaling. These structures uncommonly accumulate phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P2) while phosphatidylinositol-4-phosphate (PtdIns4P), a lipid normally concentrated in the PC, is excluded. We show that INPP5E, a phosphoinositide-associated phosphatase responsible for PtdIns4P generation, is a partner of ATG16L1 in this context. Perturbation of the ATG16L1-IFT20 complex alters INPP5E trafficking and proper function at the ciliary membrane. Altogether, these results reveal a novel autophagyindependent function of ATG16L1 that contributes to proper PC dynamics and function.
Article The autophagy protein ATG16L1 cooperates with IFT20 and INPP5E to regulate the turnover of phosphoinositides at the primary cilium Graphical abstract Highlights d ATG16L1 regulates ciliogenesis independently of macro-autophagy d ATG16L1 interacts with ciliary protein IFT20 via WD40 domain to regulate ciliogenesis d ATG16L1 interacts with the phosphoinositide-associated phosphatase INPP5E d Loss of ATG16L1 interaction with INPP5E leads to a default of PI4P at the primary cilium In brief Boukhalfa et al. report a non-canonical role for autophagy protein ATG16L1 during primary cilium biogenesis. ATG16L1 interacts with IFT20 and INPP5E to regulate elongation of the primary cilium and primary-cilium-dependent signaling. Deletion of the WD40 domain of ATG16L1 impairs ciliogenesis but not autophagy. SUMMARY The primary cilium (PC) regulates signalization linked to external stress sensing. Previous works established a functional interplay between the PC and the autophagic machinery. When ciliogenesis is promoted by serum deprivation, the autophagy protein ATG16L1 and the ciliary protein IFT20 are co-transported to the PC. Here, we demonstrate that IFT20 and ATG16L1 are part of the same complex requiring the WD40 domain of ATG16L1 and a Y-E-F-I motif in IFT20. We show that ATG16L1-deficient cells exhibit aberrant ciliary structures , which accumulate PI4,5P2, whereas PI4P, a lipid normally concentrated in the PC, is absent. Finally, we demonstrate that INPP5E, a phosphoinositide-associated phosphatase responsible for PI4P generation, interacts with ATG16L1 and that a perturbation of the ATG16L1/IFT20 complex alters its trafficking to the PC. Altogether, our results reveal a function of ATG16L1 in ciliary lipid and protein trafficking, thus directly contributing to proper PC dynamics and functions.
Influenza virus infections are major public health threats due to their high rates of morbidity and mortality. Upon influenza virus entry, host cells experience modifications of endomembranes, including those used for virus trafficking and replication. Here we report that influenza virus infection modifies mitochondrial morphodynamics by promoting mitochondria elongation and altering endoplasmic reticulum-mitochondria tethering in host cells. Expression of the viral RNA recapitulates these modifications inside cells. Virus induced mitochondria hyper-elongation was promoted by fission associated protein DRP1 relocalization to the cytosol, enhancing a pro-fusion status. We show that altering mitochondrial hyper-fusion with Mito-C, a novel pro-fission compound, not only restores mitochondrial morphodynamics and endoplasmic reticulum-mitochondria contact sites but also dramatically reduces influenza replication. Finally, we demonstrate that the observed Mito-C antiviral property is directly connected with the innate immunity signaling RIG-I complex at mitochondria. Our data highlight the importance of a functional interchange between mitochondrial morphodynamics and innate immunity machineries in the context of influenza viral infection.

Lab head

Etienne Morel
  • Cell Biology, Growth and Signaling Department
About Etienne Morel
  • Inserm Research Director (DR2); group-leader of "Autophagy pathway and intracellular compartments dynamics" research team in the cell biology department of Institut Necker Enfants Malades (Inserm U1151, Paris), Université de Paris.

Members (3)

Nicolas Dupont
  • Institut Necker Enfants-Malades
Aurore Claude-Taupin
  • Institut Necker Enfants-Malades
Juliane Da Graça
  • Institut Necker Enfants-Malades
Patrice Codogno
Patrice Codogno
  • Not confirmed yet

Alumni (6)

Anna Chiara Nascimbeni
  • French Institute of Health and Medical Research
Asma Boukhalfa
  • Tufts Medical Center
Naima Zemirli
  • Institut Necker Enfants-Malades
Yennifer Avalos
  • University of Santiago, Chile