Defining the role of β-cell IRE1α/XBP1 pathway and its gene regulatory network components in non-obese diabetic mice

Hugo Lee, Khagani Eynullazada, Qiaodan Ou, Junha Shin, Sushmita Roy and Feyza Engin ()
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Hugo Lee: School of Medicine and Public Health, Department of Biomolecular Chemistry, University of Wisconsin-Madison
Khagani Eynullazada: School of Medicine and Public Health, Wisconsin Institute for Discovery, University of Wisconsin-Madison
Qiaodan Ou: School of Medicine and Public Health, Department of Biomolecular Chemistry, University of Wisconsin-Madison
Junha Shin: School of Medicine and Public Health, Wisconsin Institute for Discovery, University of Wisconsin-Madison
Sushmita Roy: School of Medicine and Public Health, Wisconsin Institute for Discovery, University of Wisconsin-Madison
Feyza Engin: School of Medicine and Public Health, Department of Biomolecular Chemistry, University of Wisconsin-Madison

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65635-w

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