Investigating the role of ER-phagy in proinsulin quality control

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Abstract Diabetes mellitus (DM) is a metabolic syndrome that is caused by deficiency in the secretion of insulin, which is a peptide hormone that is secreted by pancreatic β-cells to regulate the uptake of blood glucose. The insulin precursor proinsulin is folded in the β-cell endoplasmic reticulum (ER). When properly folded, proinsulin exits the ER and traffics to the Golgi and into secretory granules where it is proteolytically processed to form bioactive insulin, destined for secretion. Defects in this process can directly result in DM. This is exemplified during a condition called Mutant INS-gene-induced Diabetes Youth (MIDY), which is an early-onset diabetic condition caused by expression of a mutant proinsulin. MIDY mutant proinsulins exert a toxic gain-of-function on wildtype (WT) proinsulin folding and maturation because when they misfold, they form high-molecular weight, detergent-insoluble aggregates that also entrap WT proinsulin in the ER, thereby decreasing insulin secretion. Decreased insulin secretion results in compensatory upregulation in even more WT and mutant proinsulin, causing ER stress and β-cell demise. We have recently found that the ER-coupled autophagy (ER- phagy) pathway is required for degradation of MIDY proinsulin aggregates. This process depends on the ER- phagy receptor RTN3. Our unpublished findings now suggest that the ER membrane protein PGRMC1 is a RTN3-binding partner that functions as a cargo receptor to recruit MIDY proinsulin to RTN3 for disposal. PGRMC1 physically interacts with both RTN3 and mutant proinsulin, demonstrating that the PGRMC1-RTN3 complex acts as the nexus between MIDY proinsulin and the ER-phagy pathway. Strikingly, pharmacological impairment of PGRMC1 increases proinsulin secretion. We therefore hypothesize that PGRMC1 complexes with RTN3 to recruit mutant proinsulin into the ER-phagy pathway (Aim 1), and that impairing the RTN3- PGRMC1 complex triggers WT proinsulin secretion in physiologically important MIDY models (Aim 2).