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

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 (Xbp1^β-/-) 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 Xbp1^β-/- mice exhibit reduced insulitis, apoptosis, and antigenicity phenocopying Ire1α^β-/- mice with no changes in RIDD activity. Comparative transcriptome and regulatory network analyses reveal a largely shared component between the Ire1α^β-/- and Xbp1^β-/- mice as well as network components unique to Xbp1^β-/-, 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.