RT Journal Article SR Electronic T1 Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201379 DO 10.26508/lsa.202201379 VO 5 IS 5 A1 Alexandra Papaioannou A1 Federica Centonze A1 Alice Metais A1 Marion Maurel A1 Luc Negroni A1 Matías Gonzalez-Quiroz A1 Sayyed Jalil Mahdizadeh A1 Gabriella Svensson A1 Ensieh Zare A1 Alice Blondel A1 Albert C Koong A1 Claudio Hetz A1 Rémy Pedeux A1 Michel L Tremblay A1 Leif A Eriksson A1 Eric Chevet YR 2022 UL https://www.life-science-alliance.org/content/5/5/e202201379.abstract AB 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.