Cells Deploy a Two-Pronged Strategy to Rectify Misfolded Proinsulin Aggregates

• Published in: Molecular cell Vol. 75; no. 3; pp. 442 - 456.e4
• Main Authors: Cunningham, Corey N., Williams, Jeffrey M., Knupp, Jeffrey, Arunagiri, Anoop, Arvan, Peter, Tsai, Billy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.08.2019
• Subjects: aggregates; Autophagy - genetics; Carrier Proteins - genetics; Diabetes Mellitus - genetics; Diabetes Mellitus - pathology; endoplasmic reticulum; Endoplasmic Reticulum - genetics; ER-phagy; HEK293 Cells; HSP70 Heat-Shock Proteins - genetics; Humans; Insulin - biosynthesis; Insulin - genetics; Membrane Proteins - genetics; mutant proinsulin; Mutation - genetics; Nerve Tissue Proteins - genetics; Proinsulin - biosynthesis; Proinsulin - genetics; Protein Aggregates - genetics; Protein Folding; protein quality control; reticulon; RNA, Small Interfering - genetics; reticulon; protein quality control; aggregates; mutant proinsulin; ER-phagy; endoplasmic reticulum
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.05.011

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. [Display omitted] •Akita mutant proinsulin forms detergent-insoluble aggregates•Akita aggregate formation is actively prevented by the ER-resident chaperone Grp170•RTN3-dependent ER-phagy clears Akita and other prohormone aggregates•RTN-mediated clearance of Akita aggregates partially restores WT proinsulin secretion To clarify how prohormone aggregates in the endoplasmic reticulum (ER) are removed, Cunningham et al. identified two distinct mechanisms. Specifically, the ER luminal chaperone Grp170 acts to prevent aggregate formation, while an RTN3-dependent ER-phagy pathway clears the buildup of the aggregates via an ER-to-lysosome degradation route.