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Vps13 is required for the packaging of the ER into autophagosomes during ER-phagy

Chen, S., Mari, M., Parashar, S., Liu, D., Cui, Y., Reggiori, F., Novick, P. J. & Ferro-Novick, S., 4-Aug-2020, In : Proceedings of the National Academy of Sciences of the United States of America. 117, 31, p. 18530-18539 10 p.

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DOI

Endoplasmic reticulum (ER) macroautophagy (hereafter called ER-phagy) uses autophagy receptors to selectively degrade ER domains in response to starvation or the accumulation of aggregation-prone proteins. Autophagy receptors package the ER into autophagosomes by binding to the ubiquitin-like yeast protein Atg8 (LC3 in mammals), which is needed for autophagosome formation. In budding yeast, cortical and cytoplasmic ER-phagy requires the autophagy receptor Atg40. While different ER autophagy receptors have been identified, little is known about other components of the ER-phagy machinery. In an effort to identify these components, we screened the genome-wide library of viable yeast deletion mutants for defects in the degradation of cortical ER following treatment with rapamycin, a drug that mimics starvation. Among the mutants we identified was vps13Δ. While yeast has one gene that encodes the phospholipid transporter VPS13, humans have four vacuolar protein-sorting (VPS) protein 13 isoforms. Mutations in all four human isoforms have been linked to different neurological disorders, including Parkinson's disease. Our findings have shown that Vps13 acts after Atg40 engages the autophagy machinery. Vps13 resides at contact sites between the ER and several organelles, including late endosomes. In the absence of Vps13, the cortical ER marker Rtn1 accumulated at late endosomes, and a dramatic decrease in ER packaging into autophagosomes was observed. Together, these studies suggest a role for Vps13 in the sequestration of the ER into autophagosomes at late endosomes. These observations may have important implications for understanding Parkinson's and other neurological diseases.

Original languageEnglish
Pages (from-to)18530-18539
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number31
Early online date20-Jul-2020
Publication statusPublished - 4-Aug-2020

ID: 129723041