Abstract
Unfolded protein response is a dynamic signalling pathway that is involved in maintenance of proteostasis and cellular homeostasis. IRE1, a transmembrane signaling protein that represents the start point of one of the UPR signaling cascades, which is highly conserved. IRE1 is endowed with kinase and endoribonuclease activities. Activation of Kinase domain of IRE1 by trans-autophosphorylation leads to activation of its RNAse domain. RNAse domain performs atypical splicing of Xbp1 mRNA and degradation of mRNAs by an effector function known as Regulated IRE1 Dependent Decay (RIDD). The regulation of distinctive nature of IRE1 ribonuclease function is possibly mediated by a dynamic protein structure UPRosome, which is an assembly of huge number of proteins on IRE1. Here, we reported that Bid is a novel recruit to UPRosome, which modulates IRE1 activity. Bid physically interacts with IRE1 and controls its phosphorylation levels in a negative manner. Bid overexpression displayed reduced phosphorylation levels of IRE1 and JNK, a downstream target of IRE1. Bid knockdown cells showed slightly enhanced IRE1 phosphorylation along with phosphorylation of JNK. Bid stimulated differential RNAse activity of IRE1 towards Xbp1 splicing and RIDD. These results establish that Bid is a part of UPRosome that differentially regulates IRE1 activation.