In an article published in Autophagy Reports, Prof. Molinari’s Laboratory shows how our cells remove toxic proteins by promoting the formation of contact sites between the biosynthetic compartment (the endoplasmic reticulum) and the degradative compartments (the endolysosomes).
Bellinzona – November 3rd, 2025 – DNA mutations that occur spontaneously or can be inherited, lead to the production of faulty proteins that must rapidly be eliminated to prevent cells’ intoxication. The endoplasmic reticulum (ER) is a major site of protein production. However, it does not contain a degradative machinery. Thus, faulty proteins must be transported into the cytoplasm for clearance by the proteasome. Toxic protein aggregates cannot be transported into the cytoplasm. Rather, are segregated in specialized subdomains of the ER and are eventually delivered to acidic degradative compartments (the endolysosomes). In the last few years, Molinari’s lab has mechanistically dissected these pathways, and named them ER-to-Lysosome-Associated Degradation (ERLAD). The work performed by Elisa Fasana and Ilaria Fregno in Molinari’s lab, adds yet another mechanistic piece to a puzzle, where the ER-resident lectin Calnexin, the ER-phagy receptor FAM134B, the autophagy protein LC3 and the SNARE proteins Syntaxin17 and VAM8 play a crucial role in the removal of proteasome-resistant misfolded polypeptides from the ER. Their latest study shows that misfolded proteins generate ER-endolysosomes contact sites formed by the ER protein VAPA and the endolysosomal protein RAB7 bridged by the cytosolic protein ORP1L, thereby facilitating the passage of misfolded proteins from the ER into the degradative endolysosome. Identification of these pathways at the molecular level is crucial for the design of diagnostic and therapeutic approaches aimed at contrasting progression of debilitating human diseases.
Elisa Fasana a, Ilaria Fregno a and Maurizio Molinari
