Open AccessENPL-1, theCaenorhabditis eleganshomolog of GRP94, promotes insulin secretion via regulation of proinsulin processing and maturation
Author(s) -
Agnieszka Podraza-Farhanieh,
Balasubramanian Natarajan,
Dorota Raj,
Gautam Kao,
Peter Naredi
Publication year - 2020
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.190082
Subject(s) - proinsulin , biology , caenorhabditis elegans , endoplasmic reticulum , secretion , insulin , microbiology and biotechnology , unfolded protein response , insulin receptor , mutant , chaperone (clinical) , signal transduction , endocrinology , biochemistry , gene , insulin resistance , medicine , pathology
Insulin/IGF signaling in C. elegans is crucial for proper development of the dauer larva and growth control. Mutants disturbing insulin processing, secretion and downstream signaling perturb this process and have helped identify genes that affect progression of type 2 diabetes. Insulin maturation is required for its proper secretion by pancreatic β cells. The role of the ER chaperones in insulin processing and secretion needs further study. We show that the Caenorhabditis elegans ER chaperone ENPL-1/GRP94/HSP90B1, acts in dauer development by promoting insulin secretion and signaling. Processing of a proinsulin likely involves binding between the two proteins via a specific domain. We show that in enpl-1 mutants, an unprocessed insulin exits the ER lumen and is found in dense core vesicles, but is not secreted. The high ER stress in enpl-1 mutants does not cause the secretion defect. Importantly, increased ENPL-1 levels result in increased secretion. Taken together, our work indicates that ENPL-1 operates at the level of insulin availability and is an essential modulator of insulin processing and secretion.