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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.

SUBMITTER: Haataja L

PROVIDER: S-EPMC8316239 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Distinct states of proinsulin misfolding in MIDY.

Haataja Leena L Arunagiri Anoop A Hassan Anis A Regan Kaitlin K Tsai Billy B Dhayalan Balamurugan B Weiss Michael A MA Liu Ming M Arvan Peter P

Cellular and molecular life sciences : CMLS 20210710 16

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 ...[more]

PMID: 34245311

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Project description:BackgroundLatent autoimmune diabetes in adults (LADA) is characterized by autoimmunity, late-onset and intermediate beta-cell deprivation rate between type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM). Herein, we investigated proinsulin (PI) secretion patterns and the endoplasmic reticulum (ER) dysfunction biomarker, PI-to-C-peptide (PI:CP) ratio, to elucidate beta-cell intrinsic pathogenesis mechanisms in different types of diabetes.MethodsTotal serum fasting PI (FPI) were measured in adult-onset and newly-diagnosed diabetes patients, including 60 T1DM, 60 LADA and 60 T2DM. Thirty of each type underwent mixed meal tolerance tests (MMTTs), and hence 120 min postprandial PI (PPI) were detected. PI:CP ratio = PI (pmol/L) ÷ CP (pmol/L) × 100%. PI-related measurements among types of diabetes were compared. Correlation between PI-related measurements and beta-cell autoimmunity were analyzed. The possibility of discriminating LADA from T1DM and T2DM with PI-related measurements were tested.ResultsFPI and PPI were significantly higher in LADA than T1DM (P<0.001 for both comparisons), but lower than those in T2DM (P<0.001 and P=0.026, respectively). Fasting PI:CP ratio was significantly higher in T1DM than both LADA and T2DM (median 3.25% vs. 2.13% and 2.32%, P=0.011 and P=0.017, respectively). In LADA, positive autoantibody numbers increased by both fasting and postprandial PI:CP ratio (P=0.007 and P=0.034, respectively). Areas under receiver operation characteristic curves (AUCROC) of FPI and PPI for discriminating LADA from adult-onset T1DM were 0.751 (P<0.001) and 0.838 (P<0.001), respectively. Between LADA and T2DM, AUCROC of FPI and PPI were 0.685 (P<0.001) and 0.741 (P=0.001), respectively.ConclusionsIn the development of autoimmune diabetes, interplays between ER stress and beta-cell autoimmunity are potentially responsible for severer beta-cell destruction. PI-related measurements could help in differentiating LADA from adult-onset T1DM and T2DM.

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Distinct states of proinsulin misfolding in MIDY.

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Distinct states of proinsulin misfolding in MIDY.

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