Dataset Information

Proteomics analysis for the study of beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE)

ABSTRACT: Appropriate tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with highly variable demand for insulin synthesis. An efficient UPR ensures a sufficient beta cell mass and secretory output but can also affect beta cell resilience to autoimmune aggression. However, the factors regulating protein homeostasis in the face of metabolic and immune challenges are insufficie tly understood. We examined beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE), a ubiquitous protease with high affinity for insulin, a putative ill-defined role in protein homeostasis, and genetic association with type 2 diabetes. IDE deficiency induces a low-level UPR in both standard and autoimmune non-obese diabetic (NOD) mice, associated with rapamycin-sensitive beta cell proliferation, as well as protection from diabetes in NOD mice. Moreover, in NOD islets, IDE deficiency specifically induces strong upregulation of regenerating islet-derived protein 2, a protein attenuating inflammation and protecting from autoimmunity. Our findings establish a role of IDE in islet cell protein homeostasis, corroborate the link between low-level UPR and proliferation, and identify an anti-inflammatory islet cell response uncovered in the absence of IDE of potential interest in autoimmune diabetes.

INSTRUMENT(S): timsTOF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Pancreatic Islet, Cell Culture

SUBMITTER: Cerina Chhuon

LAB HEAD: Ida Chiara Guerrera

PROVIDER: PXD034826 | Pride | 2024-06-16

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20150427_PeVE_100Ilots_KO1_1_2209.raw	Raw
	20150427_PeVE_100Ilots_KO1_2_2210.raw	Raw
	20150427_PeVE_100Ilots_KO1_3_2211.raw	Raw
	20150427_PeVE_100Ilots_KO2_1_2212.raw	Raw
	20150427_PeVE_100Ilots_KO2_2_2213.raw	Raw

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Publications

Islet cell stress induced by insulin-degrading enzyme deficiency promotes regeneration and protection from autoimmune diabetes.

Zhu Shuaishuai S Waeckel-Énée Emmanuelle E Oshima Masaya M Moser Anna A Bessard Marie-Andrée MA Gdoura Abdelaziz A Roger Kevin K Mode Nina N Lipecka Joanna J Yilmaz Ayse A Bertocci Barbara B Diana Julien J Saintpierre Benjamin B Guerrera Ida Chiara IC Scharfmann Raphael R Francesconi Stefania S Mauvais François-Xavier FX van Endert Peter P

iScience 20240507 6

Tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with variable demand for insulin. Here, we asked how insulin-degrading enzyme (IDE) affects beta cell adaptation to metabolic and immune stress. C57BL/6 and autoimmune non-obese diabetic (NOD) mice lacking IDE were exposed to proteotoxic, metabolic, and immune stress. IDE deficiency induced a low-level UPR with islet hypertrophy at the steady state, ra ...[more]

PMID: 38799566

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Project description:Aims/hypothesis AGEs are considered environmental contributors of type 1 diabetes, but the exact role AGEs play early in pathogenesis of the disease, remains unidentified. We aimed to reduce AGEs with the pharmacotherapy alagebrium chloride in MIN6N8 cells and early in life in NOD mice to determine its impact on beta cell immunogenicity, function, and disease progression. Methods MIN6N8 cells were cultured with AGEs with or without short-term alagebrium therapy to determine the effect on ER stress and beta cell antigen presentation via a reporter assay for protein responses in the unfolded protein response, the enzymatic activity of endoplasmic reticulum aminopeptidase-1 (ERAP1) and the immunopeptidome. To determine the effect of short-term alagebrium therapy on beta cells in vivo, female NOD mice were treated with alagebrium and insulin secretion, insulitis, and immune cell repertoire were studied. Adoptive transfer studies and diabetes progression studies were used to consider the impact of alagebrium on immune cell function and disease outcome. Results In MIN6N8 cells, alagebrium therapy inhibited the induction of endoplasmic reticulum (ER) stress and the activity of ERAP1 by AGE-modified proteins. Alagebrium treated-MIN6N8 cells did not change the MHC Class I presentation of known beta cell antigens but did induce proteomic changes related to ER homeostatic pathways. Prior to overt autoimmune diabetes, female NOD mice treated with alagebrium for 30-40 days had improved insulin secretion, reduced insulitis and amplified proportions of pancreatic CD8+ T cells, mature B cells and F4/80+ macrophages. Splenocytes from alagebrium-treated mice adoptively transferred disease to NODscid recipients and maintained interferon production in vitro. While partial protection of islets by alagebrium was seen following the adoptive transfer of activated NOD G9C8 transgenic TCR CD8+ T cells, alagebrium therapy in NOD mice did not reduce diabetes progression. Conclusions/interpretation Our data suggests that in experimental models of diabetes, short-term alagebrium treatment allows for beta cell improvement, and maintenance of immune cell function, which does not fully mitigate diabetes progression.