Autophagy is a conserved cellular degradation pathway conserved among all the eukaryotes and constitutes one of the major intracellular quality control systems. It is characterized by the enwrapping of cargoes, such as aberrant or dysfunctional proteins and protein complexes, superfluous or damaged organelles and invading pathogens, into double-membrane vesicles called autophagosomes and their delivery and recycling in digestive organelles of cells, the lysosomes/vacuoles. Because of its capacity to eliminate unwanted structures, autophagy is essential for numerous physiological functions of the cells and organisms. As a result, dysregulation of autophagy has been associated with multiple human diseases, such as neurodegenerative disorders, autoimmune diseases, myopathies, and several types of cancer.
Autophagosomes are generated by the nucleation, elongation and closure of a cistern termed phagophore. The expansion of this membrane relies on a major lipid supply and it is tightly regulated by the action of the autophagy-related (ATG) proteins. Although it is well-known which are the proteins involved in autophagy pathway, it was poorly understood which factor/s determine the transition from a phagophore into a large autophagosome.
This study has found that the Rab GTPase Ypt1 acts as a “molecular switch”, inducing the phagophore growth by coordinating the molecular machinery and the lipid supply. Authors have revealed that this event is triggered by the formation of membrane contact sites (“intracellular bridges”) between the endoplasmic reticulum and the forming phagophore, which practically tells the phagophore that the lipid influx from the endoplasmic reticulum is set and therefore the phagophore can start to elongate.
This discovery will advance our knowledge on autophagy regulation and in a long-term, it could provide new targets for the development of therapies or compounds aimed at regulating autophagy to the benefit of the human health.
This study has been developed together by researchers of F. Reggiori group (University Medical Center Groningen and Aarhus University, Denmark), in collaboration with the laboratories of C. Ungermann (Osnabrück University, Osnabrück, Germany) and J. C. Fromme (Cornell University, Ithaca, USA).
More information: Rubén Gómez-Sánchez et al, Establishment of the phagophore–ERES membrane contact site initiates phagophore elongation, Nature Structural & Molecular Biology (2025).
