Regulated Inositol Requiring Enzyme 1 dependent mRNA decay sets the threshold for dendritic cell survival

Abstract

The IRE1/XBP1 signaling pathway is part of a cellular program that protects from endoplasmic reticulum (ER) stress, but also controls development and survival of immune cells. Loss of XBP1 in splenic type 1 conventional dendritic cells (cDC1s) results in phenotypic and functional alterations without affecting cell survival. However, in mucosal cDC1s, loss of XBP1 impaired survival in a tissue specific manner - while lung cDC1s die, intestinal cDC1s survive. This was not caused by differential activation of ER stress cell death regulators CHOP or JNK. Rather, cell fate was determined by a differential ability to shut down protein synthesis via a protective ATF4-dependent integrated stress response. In addition, regulated IRE1 dependent mRNA decay (RIDD) occurred mainly in intestinal cDC1s, and compound deficiency of IRE1 endonuclease led to cDC1 loss also in the intestine. Thus, mucosal DCs differentially mount ATF4 and IRE1 dependent adaptive mechanisms to survive in the face of ER stress.