Mutant INS-gene induced diabetes of youth:proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport

摘要

Recently, a syndrome of Mutant INS-gene-induced Diabetes of Youth (MIDY, derived from one ofud26 distinct mutations) has been identified as a cause of insulin-deficient diabetes, resulting fromudexpression of a misfolded mutant proinsulin protein in the endoplasmic reticulum (ER) of insulinproducingudpancreatic beta cells. Genetic deletion of one, two, or even three alleles encoding insulinudin mice does not necessarily lead to diabetes. Yet MIDY patients are INS-gene heterozygotes;udinheritance of even one MIDY allele, causes diabetes. Although a favored explanation for the onsetudof diabetes is that insurmountable ER stress and ER stress response from the mutant proinsulinudcauses a net loss of beta cells, in this report we present three surprising and interlinked discoveries.udFirst, in the presence of MIDY mutants, an increased fraction of wild-type proinsulin becomesudrecruited into nonnative disulfide-linked protein complexes. Second, regardless of whether MIDYudmutations result in the loss, or creation, of an extra unpaired cysteine within proinsulin, Cysudresidues in the mutant protein are nevertheless essential in causing intracellular entrapment of coexpressedudwild-type proinsulin, blocking insulin production. Third, while each of the MIDYudmutants induces ER stress and ER stress response; ER stress and ER stress response alone appearudinsufficient to account for blockade of wild-type proinsulin. While there is general agreement thatudultimately, as diabetes progresses, a significant loss of beta cell mass occurs, the early eventsuddescribed herein precede cell death and loss of beta cell mass. We conclude that the molecularudpathogenesis of MIDY is initiated by perturbation of the disulfide-coupled folding pathway of wildtypeudproinsulin.