The IRE1α-endonuclease regulates PD-1 expression through a novel XBP1/miRNA-34a axis within Natural Killer cells

Activation of the IRE1-endonuclease is critical for Natural Killer (NK)-cell function. We describe a novel regulatory role for IRE1-endonuclease in fine-tuning NK-cell effector functions through an inter-connected activation of the transcription factor XBP1s and inhibition of microRNA-34a-5p (miR-34a-5p) to modulate PD-1 immune checkpoint expression. NK-cells, when exposed to cancer cells, activate IRE1-endonuclease mediated decay of miR-34a-5p. This reduces miR-34a-5p and consequently increases the expression of the target genes XBP1 and PD-1. IRE1-endonuclease activation not only enhances NK-cell effector function but also promotes PD-1 expression. PD-1 is itself directly regulated by miR-34a-5p, which binds to the 3UTR of PD-1 messenger RNA to repress PD-1 protein at the NK-cell surface. IRE1-pathway activation is impaired in the NK-cells of patients with Hodgkin Lymphoma, and miR-34a-5p and PD-1 expression are inversely correlated. The IRE1-pathway plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within NK-cells, that is disrupted in cancer patients.