Molecular Cell
Volume 75, Issue 3, 8 August 2019, Pages 442-456.e4
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Article
Cells Deploy a Two-Pronged Strategy to Rectify Misfolded Proinsulin Aggregates

https://doi.org/10.1016/j.molcel.2019.05.011Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

ER-phagy
reticulon
mutant proinsulin
aggregates
endoplasmic reticulum
protein quality control

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