Abstract
The most evolutionary conserved sensor of the Unfolded Protein Response, IRE1, signals through its cytosolic kinase and endoribonuclease (RNase) activities. IRE1 RNase can either catalyze XBP1 mRNA unconventional splicing or degrade RNAs through Regulated IRE1-Dependent Decay (RIDD). The balance between these two activities controls cells’ life and death decisions upon ER stress. The outputs of IRE1 RNase activity have been well documented, however, the mechanisms by which IRE1 triggers adaptive or death signals remain unclear. We hypothesized that XBP1 mRNA splicing and RIDD could be co-regulated by the IRE1 RNase regulatory network. We showed that the tRNA ligase RtcB which, together with IRE1, is responsible for XBP1 mRNA splicing, is tyrosine phosphorylated by c-Abl and dephosphorylated by PTP1B. We identified RtcB Y306 as a key residue which, when phosphorylated, perturbs RtcB interaction with IRE1, thereby attenuating XBP1 mRNA splicing and favoring RIDD. Our results demonstrate that the IRE1/RtcB signaling is controlled by tyrosine phosphorylation and that the nature of the stress determines cell adaptive or death outputs.
Competing Interest Statement
The authors have declared no competing interest.
