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Top-Down Proteomics of Mouse Islets With Beta Cell CPE Deletion Reveals Molecular Details in Prohormone Processing.

Authors :
Fulcher JM
Swensen AC
Chen YC
Verchere CB
Petyuk VA
Qian WJ
Source :
Endocrinology [Endocrinology] 2023 Nov 02; Vol. 164 (12).
Publication Year :
2023

Abstract

Altered prohormone processing, such as with proinsulin and pro-islet amyloid polypeptide (proIAPP), has been reported as an important feature of prediabetes and diabetes. Proinsulin processing includes removal of several C-terminal basic amino acids and is performed principally by the exopeptidase carboxypeptidase E (CPE), and mutations in CPE or other prohormone convertase enzymes (PC1/3 and PC2) result in hyperproinsulinemia. A comprehensive characterization of the forms and quantities of improperly processed insulin and other hormone products following Cpe deletion in pancreatic islets has yet to be attempted. In the present study we applied top-down proteomics to globally evaluate the numerous proteoforms of hormone processing intermediates in a β-cell-specific Cpe knockout mouse model. Increases in dibasic residue-containing proinsulin and other novel proteoforms of improperly processed proinsulin were found, and we could classify several processed proteoforms as novel substrates of CPE. Interestingly, some other known substrates of CPE remained unaffected despite its deletion, implying that paralogous processing enzymes such as carboxypeptidase D (CPD) can compensate for CPE loss and maintain near normal levels of hormone processing. In summary, our quantitative results from top-down proteomics of islets provide unique insights into the complexity of hormone processing products and the regulatory mechanisms.<br /> (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Details

Language :
English
ISSN :
1945-7170
Volume :
164
Issue :
12
Database :
MEDLINE
Journal :
Endocrinology
Publication Type :
Academic Journal
Accession number :
37967211
Full Text :
https://doi.org/10.1210/endocr/bqad160