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Cells Deploy a Two-Pronged Strategy to Rectify Misfolded Proinsulin Aggregates.
- Source :
-
Molecular cell [Mol Cell] 2019 Aug 08; Vol. 75 (3), pp. 442-456.e4. Date of Electronic Publication: 2019 Jun 05. - Publication Year :
- 2019
-
Abstract
- Insulin gene coding sequence mutations are known to cause mutant INS-gene-induced diabetes of youth (MIDY), yet the cellular pathways needed to prevent misfolded proinsulin accumulation remain incompletely understood. Here, we report that Akita mutant proinsulin forms detergent-insoluble aggregates that entrap wild-type (WT) proinsulin in the endoplasmic reticulum (ER), thereby blocking insulin production. Two distinct quality-control mechanisms operate together to combat this insult: the ER luminal chaperone Grp170 prevents proinsulin aggregation, while the ER membrane morphogenic protein reticulon-3 (RTN3) disposes of aggregates via ER-coupled autophagy (ER-phagy). We show that enhanced RTN-dependent clearance of aggregated Akita proinsulin helps to restore ER export of WT proinsulin, which can promote WT insulin production, potentially alleviating MIDY. We also find that RTN3 participates in the clearance of other mutant prohormone aggregates. Together, these results identify a series of substrates of RTN3-mediated ER-phagy, highlighting RTN3 in the disposal of pathogenic prohormone aggregates.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Autophagy genetics
Diabetes Mellitus pathology
Endoplasmic Reticulum genetics
HEK293 Cells
Humans
Insulin biosynthesis
Mutation genetics
Proinsulin biosynthesis
Protein Aggregates genetics
Protein Folding
RNA, Small Interfering genetics
Carrier Proteins genetics
Diabetes Mellitus genetics
HSP70 Heat-Shock Proteins genetics
Insulin genetics
Membrane Proteins genetics
Nerve Tissue Proteins genetics
Proinsulin genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 75
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 31176671
- Full Text :
- https://doi.org/10.1016/j.molcel.2019.05.011