TY - JOUR T1 - Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201379 VL - 5 IS - 5 SP - e202201379 AU - Alexandra Papaioannou AU - Federica Centonze AU - Alice Metais AU - Marion Maurel AU - Luc Negroni AU - Matías Gonzalez-Quiroz AU - Sayyed Jalil Mahdizadeh AU - Gabriella Svensson AU - Ensieh Zare AU - Alice Blondel AU - Albert C Koong AU - Claudio Hetz AU - Rémy Pedeux AU - Michel L Tremblay AU - Leif A Eriksson AU - Eric Chevet Y1 - 2022/05/01 UR - https://www.life-science-alliance.org/content/5/5/e202201379.abstract N2 - ER stress is mediated by three sensors and the most evolutionary conserved IRE1α signals through its cytosolic kinase and endoribonuclease (RNase) activities. IRE1α 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 IRE1α RNase activity have been well documented; however, the precise mechanisms controlling whether IRE1α 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 IRE1α 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 IRE1α, thereby attenuating XBP1 mRNA splicing. Our results demonstrate that the IRE1α RNase regulatory network is dynamically fine-tuned by tyrosine kinases and phosphatases upon various stresses and that the extent of RtcB tyrosine phosphorylation determines cell adaptive or death outputs. ER -