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

Area of Science:

• Cellular Biology
• Molecular Medicine
• Endocrinology

Background:

• Mutations in the insulin gene cause mutant INS-gene-induced diabetes of youth (MIDY).
• Cellular mechanisms preventing misfolded proinsulin accumulation are not fully understood.
• Akita mutant proinsulin aggregates in the endoplasmic reticulum (ER), trapping wild-type (WT) proinsulin and halting insulin production.

Purpose of the Study:

• To elucidate the cellular pathways that prevent misfolded proinsulin accumulation.
• To investigate the roles of Grp170 and reticulon-3 (RTN3) in managing proinsulin aggregation.
• To explore the therapeutic potential of enhancing RTN3-mediated clearance for MIDY.

Main Methods:

• Investigated the aggregation of Akita mutant proinsulin in the ER.
• Examined the function of ER luminal chaperone Grp170 in preventing aggregation.
• Assessed the role of ER membrane protein RTN3 in aggregate clearance via ER-phagy.
• Evaluated the impact of enhanced RTN3 activity on WT proinsulin export and production.

Main Results:

• Akita mutant proinsulin forms detergent-insoluble aggregates that sequester WT proinsulin in the ER.
• Grp170 acts as a chaperone to prevent proinsulin aggregation.
• RTN3 mediates the disposal of these aggregates through ER-phagy.
• Enhanced RTN3-dependent clearance restores ER export of WT proinsulin, promoting insulin production and potentially alleviating MIDY.
• RTN3 also clears other mutant prohormone aggregates.

Conclusions:

• Two quality-control mechanisms, Grp170 and RTN3-mediated ER-phagy, combat proinsulin aggregation.
• RTN3 plays a critical role in clearing pathogenic prohormone aggregates.
• Targeting RTN3-mediated ER-phagy presents a potential therapeutic strategy for MIDY and other prohormone-related disorders.