Endoplasmic reticulum tubules limit the size of misfolded protein condensates

eLife

Shuliang Chen¹  Smriti Parashar¹  Susan Ferro-Novick¹  Ravi Chidambaram¹  Nathan C Shaner²  Gerard G Lambert²  Matthew Wortham³  Jesse C Hay⁴  Christina R Liem⁵  Eric Griffis⁶ 

[1] Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, United States;Department of Neurosciences, University of California at San Diego, La Jolla, California, United States;Department of Pediatrics, Pediatric Diabetes Research Center, University of California at San Diego, La Jolla, California, United States;Division of Biological Sciences and Center for Structural & Functional Neuroscience, University of Montana, Missoula, United States;Division of Biological Sciences, University of California at San Diego, La Jolla, California, United States;Nikon Imaging Center, University of California at San Diego, La Jolla, California, United States;

关键词: ER-phagy;    protein quality control;    misfolded prohormones;    SEC24C;    Lunapark;    ER structure;    misfolded neuropeptides;    Other;   

DOI  :  10.7554/eLife.71642

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY