Abstract Signalling by the Unfolded Protein Response (UPR) or by the Death Receptors (DR) represents cellular stress pathways frequently activated towards pro-tumoral outputs in cancer. Experimental evidence has highlighted functional links between the UPR and the DR TRAIL-R1/2. Herein, we demonstrate that the UPR sensor IRE1 controls the expression of CD95/Fas, another DR, and its cell death-inducing ability. Whereas CD95 is not a general determinant of ER stress-induced cell death, IRE1 RNase activity inhibition increased CD95 expression and exacerbated CD95L-induced cell death in glioblastoma (GB) and Triple-Negative Breast Cancer (TNBC) cell lines. In accordance, CD95 mRNA was identified as a target of Regulated IRE1-Dependent Decay of RNA (RIDD). Moreover, CD95 expression is elevated in TNBC and GB human tumours exhibiting low RIDD activity. Surprisingly, CD95 expression is also lower in XBP1s-low human tumour samples. We show that IRE1 RNase inhibition led to CD95 expression attenuation and reduced CD95-mediated hepatic toxicity in mice. In addition, overexpression of XBP1s increased CD95 expression and sensitized GB and TNBC cells to CD95L-induced cell death. Overall, these results demonstrate the tight IRE1-mediated control of CD95-dependent cell death signals in a dual manner through both RIDD and XBP1s, and they identify a novel, pharmacologically actionable link between IRE1 and CD95 signalling.

IRE1 RNase controls CD95-mediated cell death