The molecular mechanisms behind membrane trafficking
Membrane trafficking keeps cells organized and allows them to communicate. When this system fails, inherited diseases can arise because key trafficking components no longer work properly.
Signalling and membrane trafficking
By studying phosphoinositides at the Golgi, we uncovered a link between the GTPase ARF and phosphoinositide metabolism, identifying a specific PI4 kinase as a novel ARF effector. We showed that FAPP proteins control Golgi‑to‑plasma membrane transport and glycosphingolipid (GSL) synthesis through FAPP2‑mediated non‑vesicular transfer of glucosylceramide, reshaping the view of GSL flux and highlighting FAPP2 as a candidate target in GSL storage diseases, such as Fabry disease.
At endosomes, we defined the role of OCRL, a PI(4,5)P2 5‑phosphatase mutated in Lowe syndrome, a rare X‑linked disorder with eye, kidney and neurological defects. Our work showed that OCRL is essential for multiple endosomal routes, including megalin trafficking in kidney tubules, and that its loss causes actin dysregulation, PI(4,5)P2 build‑up at lysosomes and blocked autophagosome‑lysosome fusion; using small‑molecule screens, we identified a compound that corrects these defects in cells, organoids and animal models, now moving toward a clinical trial planned for 2026.
Membrane contact sites (MCSs)
MCSs are zones where two organelles come into close proximity, most often between the endoplasmic reticulum (ER) and mitochondria, endosomes or the Golgi, enabling rapid exchange of lipids and ions. We developed tools to visualize and tune the stability of these contacts and used them to identify new molecular players at ER–Golgi, ER–endosome and ER–mitochondria MCSs, with a focus on how their dysfunction contributes to genetic such as Amyotrophi Lateral Sclerosis 8 (ALS8), but also to inflammatory diseases.
ALS8, a motor neuron disease caused by mutations in the MCS protein VAPB, revealed how contact sites shape neuronal health: VAPB depletion increases Golgi and acidic‑vesicle PI4P and impairs neurite extension, defects that can be rescued by lowering PI4P, and a disease‑linked VAPB mutant damages mitochondria via altered ER–mitochondria contacts. We also discovered that disturbed ER–endosome contacts can trigger NLRP3 inflammasome activation on early endosomes and IL‑1β release, and we are now using high‑content screens of small‑molecule and siRNA libraries to find druggable nodes that modulate this pathway.
Learning from viruses and piloting them
Pathogens have been powerful teachers in cell biology, and we are harnessing them to understand and manipulate membrane dynamics. By examining how coronaviruses, including SARS‑CoV‑2, remodel the ER to generate double‑membrane vesicles, we are shedding light on how autophagosomes form at specialized ER sites that share many features with virus‑induced membranes.
We are also mapping the intracellular journey of adeno‑associated viruses (AAVs), key vectors for gene therapy that still require high, sometimes toxic doses to be effective. By dissecting the endocytic and trafficking routes that AAVs follow to reach the nucleus, we have uncovered an unexpected pathway and identified membrane‑trafficking factors that either support or hinder this journey, paving the way for strategies that remove cellular barriers and boost the safety and efficiency of AAV‑based therapies.
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My work has focused on the molecular mechanisms controlling intracellular membrane trafficking, a process that is crucial for the maintenance of cell organization, organelle homeostasis, and for intercellular communication. In recent years, our research has aimed to develop therapeutic strategies to cure inherited diseases.
Additional Funding
- FNIH - Monitoring and piloting the intracellular trafficking of AAVs in control and rare disease cell models (2022-2025)
- Dysregulation of endosome identity in inflammation and cancer: the role of endosomal NLRP3 activation in breast cancer (2024-2028), AIRC
- FIS: COMPELLING: COronavirus-induced Membrane ProtEin and Lipid remodelLING: how beta-coronaviruses exploit the host cell machinery for viral replication and propagation (2024-2028)