Insulin-degrading enzyme regulates mRNA processing and interacts with the CCR4-NOT complex

Insulin-degrading enzyme is a zinc metallo protease degrading low molecular weight substrates including insulin. Ubiquitous expression, high evolutionary conservation, upregulation of Ide in stress situations, and literature findings suggest a broader function of Ide in cell physiology and protein homeostasis that remains to be elucidated. We used proteomics and transcriptomics approaches searching for leads related to a broader role of Ide in protein homeostasis. We combined an analysis of the proteome and single-cell transcriptome of Ide+/+ and Ide-/- pancreatic islet cells with an examination of the interactome of human cytosolic Ide using proximity biotinylation. We observe an upregulation of pathways related to RNA processing, translation and splicing in Ide+/+ relative to Ide-/- islet cells. Corroborating these results and providing a potential mechanistic explanation, proximity biotinylation reveals interaction of Ide with several subunits of CCR4-NOT, a key mRNA deadenylase regulating gene expression "from birth to death". We propose a speculative model in which human and murine Ide and CCR4-NOT cooperate to control protein expression in proteotoxic and metabolic stress situations through cooperation between their deadenylase and protease functions. Overall design: Islets were isolated and dissociated into single cell suspensions from the pancreas of 3 Ide-/- and 3 Ide+/+ C57BL/6 mice. Cell capture and cDNA library amplification were carried out using the BD Rhapsody system.