Insulin-Degrading Enzyme Regulates mRNA Processing and May Interact with the CCR4-NOT Complex

TL;DR

This study explores how insulin-degrading enzyme (Ide) may regulate mRNA processing and interact with the CCR4-NOT complex to manage protein homeostasis during stress.

Contribution

The paper reveals a novel role for Ide in RNA processing and suggests a functional interaction with the CCR4-NOT complex.

Findings

Ide+/+ islet cells show upregulated RNA processing, translation, and splicing pathways compared to Ide−/− cells.

Proximity biotinylation shows Ide interacts with subunits of the CCR4-NOT complex, a key mRNA deadenylase.

A speculative model proposes Ide and CCR4-NOT cooperate to control protein expression during stress.

Abstract

Insulin-degrading enzyme is a zinc metalloprotease that degrades 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 to search 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 cooperate with CCR4-NOT to control protein expression in proteotoxic and metabolic stress situations through cooperation between their deadenylase and protease functions.

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