control of precursor maturation and disposal is an early regulative mechanism in the normal insulin production of pancreatic β-cells控制前体的成熟和处置是一个早期的调控机制在正常胰岛素的胰腺β-cells的生产.pdfVIP

Control of Precursor Maturation and Disposal Is an Early Regulative Mechanism in the Normal Insulin Production of Pancreatic b-Cells 1 2 1¤ 1¤ 1 1 Jie Wang *, Ying Chen , Qingxin Yuan , Wei Tang , Xiaoping Zhang , Kwame Osei 1 Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America, 2 Departments of Neurobiology and Neurology, The University of Chicago, Chicago, Illinois, United States of America Abstract The essential folding and maturation process of proinsulin in b-cells is largely uncharacterized. To analyze this process, we improved approaches to immunoblotting, metabolic labeling, and data analysis used to determine the proportion of monomers and non-monomers and changes in composition of proinsulin in cells. We found the natural occurrence of a large proportion of proinsulin in various non-monomer states, i.e., aggregates, in normal mouse and human b-cells and a striking increase in the proportion of proinsulin non-monomers in Ins2+/Akita mice in response to a mutation (C96Y) in the insulin 2 (Ins2) gene. Proinsulin emerges in monomer and abundant dual-fate non-monomer states during nascent protein synthesis and shows heavy and preferential ATP/redox-sensitive disposal among secretory proteins during early post- translational processes. These findings support the preservation of proinsulin’s aggregation-prone nature and low relative folding rate that permits the plentiful production of non-monomer forms with incomplete folding. Thus, in normal mouse/ human b-cells, proinsulin’s integrated maturation and degradation processes maintain a balance of natively and non- natively folded states, i.e., proinsulin homeostasis