GSE113214
The IRE1-XBP1 pathway promotes natural killer cell responses against viral infection and cancer by regulation of c-Myc
Natural killer (NK) cells are critical mediators of host immunity against infectious disease and cancer. The intrinsic regulators of NK cells are not fully understood. Here, we demonstrate that the ER stress sensor inositol-requiring enzyme 1 (IRE1a) and its substrate transcription factor X-box-binding protein 1 (XBP1) critically drive NK cell-mediated responses against viral infection and tumors. IRE1a and XBP1 were essential for the robust expansion of activated mouse and human NK cells. Transcriptome analysis revealed the transcription factor c-Myc as a novel and direct target of XBP1 for downstream regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1a downregulated c-Myc, whereas overexpression of XBP1 resulted in c-Myc hyperactivation. NK cells lacking c-Myc demonstrated a functional deficit comparable to IRE1a or XBP1 deficiency. Overall, our study identifies a novel IRE1-XBP1-cMyc axis in NK cell immunity, providing new insight into the host immune response against infection and cancer. Overall design: Transcriptome analysis of activated and quiescent NK cells (WT and IRE1 KO)