Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs

ER stress is mediated by three sensors and the most evolutionary conserved IRE1 alpha signals through its cytosolic kinase and endoribonuclease (RNase) activities. IRE1 alpha RNase activity can either catalyze the initial step of XBP1 mRNA unconventional splicing or degrade a number of RNAs through regulated IRE1-dependent decay. Until now, the biochemical and biological outputs of IRE1 alpha RNase activity have been well documented; however, the precise mechanisms controlling whether IRE1 alpha signaling is adaptive or pro-death (terminal) remain unclear. We investigated those mechanisms and hypothesized that XBP1 mRNA splicing and regulated IRE1-dependent decay activity could be co-regulated by the IRE1 alpha RNase regulatory network. We identified that RtcB, the tRNA ligase responsible for XBP1 mRNA splicing, is tyrosine-phosphorylated by c-Abl and dephosphorylated by PTP1B. Moreover, we show that the phosphorylation of RtcB at Y306 perturbs RtcB interaction with IRE1 alpha, thereby attenuating XBP1 mRNA splicing. Our results demonstrate that the IRE1 alpha RNase regulatory network is dynamically finetuned by tyrosine kinases and phosphatases upon various stresses and that the extent of RtcB tyrosine phosphorylation determines cell adaptive or death outputs.