Defining the role of β-cell IRE1α/XBP1 pathway and its gene regulatory network components in non-obese diabetic mice
Year: 2025
Type: article
Abstract: The unfolded protein response sensor, IRE1α, acts through its regulated IRE1α-dependent decay (RIDD) activity or transcription factor XBP1 to determine cell fate and survival. While blunting RIDD activity prevents diabetes in type 1 diabetes preclinical model non-obese diabetic mice, β-cell-specific function of XBP1 at different stages of disease remains unknown. Here we show that deletion of Xbp1 in β-cells (Xbp1β-/-) of non-obese diabetic mice before insulitis is protective against diabetes. Histological and transcriptomic analyses indicate that following a transient loss of maturity, β-cells of Xbp1β-/- mice exhibit reduced insulitis, apoptosis, and antigenicity phenocopying Ire1αβ-/- mice with no changes in RIDD activity. Comparative transcriptome and regulatory network analyses reveal a largely shared component between the Ire1αβ-/- and Xbp1β-/- mice as well as network components unique to Xbp1β-/-, indicative of IRE1α-independent roles of XBP1. Our findings define the role of β-cell IRE1α/XBP1 and identify previously unrecognized regulatory networks and nodes of this pathway. Modulating the unfolded protein response (UPR) can induce protective dedifferentiation of β-cells in non-obese diabetic mice. Here, the authors show that β-cell deletion of UPR transcription factor XBP1 is protective against diabetes in these mice and characterize the relevant regulatory networks.
Source: Nature Communications
Authors: Hugo Lee, Khagani Eynullazada, Qiaodan Ou, Junha Shin, Sushmita Roy, Feyza Engin
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: University of Wisconsin-Madison, University of Wisconsin Carbone Cancer Center, Juvenile Diabetes Research Foundation United States of America, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W4416718983