Distinct states of proinsulin misfolding in MIDY

Abstract

A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) interchain disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)-Cys(A11), is not required for anterograde trafficking, i.e., a lose-A6/A11 mutant [Cys(A6), Cys(A11) both converted to Ser] is well secreted. Nevertheless, an unpaired Cys(A11) can participate in disulfide mispairings, causing ER retention of proinsulin. Among the many missense mutations causing the syndrome of Mutant INS gene-induced Diabetes of Youth (MIDY), all seem to exhibit perturbed proinsulin disulfide bond formation. Here we have examined a series of seven MIDY mutants [including G(B8)V, Y(B26)C, L(A16)P, H(B5)D, V(B18)A, R(Cpep+2)C, E(A4)K], six of which are essentially completely blocked in export from the ER in pancreatic β-cells. Three of these mutants, however, must disrupt the Cys(A6) Cys(A11) pairing to expose a critical unpaired cysteine thiol perturbation of proinsulin folding and ER export, because when introduced into the proinsulin lose-A6/A11 background, these mutants exhibit native-like disulfide bonding and improved trafficking. This maneuver also ameliorates dominant-negative blockade of export of co-expressed wild-type proinsulin. A growing molecular understanding of proinsulin misfolding may permit allele-specific pharmacological targeting for some MIDY mutants.

Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes

“…Although highly associated with both T1 and T2D, it remains uncertain whether proinsulin processing defects induce or result from disease (Sharma et al, 2021). The importance of insulin processing to β-cell function is evident from the numerous mutations in the human insulin gene leading to hormone misfolding, that cause mutant INS-geneinduced diabetes of youth (MIDY) (Haataja et al, 2021). Importantly, serine/threonine-protein kinase/endoribonuclease IRE1 (IRE1), a regulator of UPR, is required for enhancing insulin biosynthesis in the ER in response to transient glucose, however, in chronic glucotoxic conditions it becomes hyperactive and enhances ER stress (Lipson et al, 2006).…”