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 (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.