Endoplasmic reticulum tubules limit the size of misfolded protein condensates
Autor: | Matthew Wortham, Eric R. Griffis, Susan Ferro-Novick, Smriti Parashar, Ravi Chidambaram, Shuliang Chen, Christina R Liem, Gerard G. Lambert, Nathan C. Shaner, Jesse C. Hay |
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Rok vydání: | 2021 |
Předmět: |
Protein Folding
ER-phagy endocrine system diseases Mutant Endoplasmic Reticulum Mice 0302 clinical medicine cell biology Biology (General) SEC24C Receptor COPII Proinsulin 0303 health sciences Tumor Chemistry General Neuroscience General Medicine Cell biology Medicine Protein folding hormones hormone substitutes and hormone antagonists endocrine system Cell signaling QH301-705.5 Science Knockout Protein subunit ER structure Lunapark General Biochemistry Genetics and Molecular Biology Cell Line Protein Aggregates 03 medical and health sciences Autophagy Animals Humans protein quality control 030304 developmental biology General Immunology and Microbiology Endoplasmic reticulum Membrane Proteins misfolded neuropeptides HEK293 Cells nervous system Other Biochemistry and Cell Biology Lysosomes Carrier Proteins misfolded prohormones 030217 neurology & neurosurgery |
Zdroj: | eLife, Vol 10 (2021) |
ISSN: | 2050-084X |
Popis: | The endoplasmic reticulum (ER) is composed of sheets and tubules. Here we report that the COPII coat subunit, SEC24C, works with the long form of the tubular ER-phagy receptor, RTN3, to target dominant-interfering mutant proinsulin Akita puncta to lysosomes. When the delivery of Akita puncta to lysosomes was disrupted, large puncta accumulated in the ER. Unexpectedly, photobleach analysis indicated that Akita puncta behaved as condensates and not aggregates, as previously suggested. Akita puncta enlarged when either RTN3 or SEC24C were depleted, or when ER sheets were proliferated by either knocking out Lunapark or overexpressing CLIMP63. Other ER-phagy substrates that are segregated into tubules behaved like Akita, while a substrate (type I procollagen) that is degraded by the ER-phagy sheets receptor, FAM134B, did not. Conversely, when ER tubules were augmented in Lunapark knock-out cells by overexpressing reticulons, ER-phagy increased and the number of large Akita puncta was reduced. Our findings imply that segregating cargoes into tubules has two beneficial roles. First, it localizes mutant misfolded proteins, the receptor, and SEC24C to the same ER domain. Second, physically restraining condensates within tubules, before they undergo ER-phagy, prevents them from enlarging and impacting cell health. |
Databáze: | OpenAIRE |
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