OLIGOMERIZATION AND PHOSPHORYLATION OF THE IRE1P KINASE DURING INTRACELLULAR SIGNALING FROM THE ENDOPLASMIC-RETICULUM TO THE NUCLEUS

The transmembrane kinase Ire1p is required for activation of the unfol ded protein response (UPR), the increase in transcription of genes enc oding endoplasmic reticulum (ER) resident proteins that occurs in resp onse to the accumulation of unfolded proteins in the ER, Ire1p spans t he ER membrane (or the nuclear membrane with which the ER is continuou s), with its kinase domain localized in the cytoplasm or in the nucleu s. Consistent with this arrangement, it has been proposed that Ire1p s enses the accumulation of unfolded proteins in the ER and transmits th e signal across the membrane toward the transcription machinery, possi bly by phosphorylating downstream components of the UPR pathway, Molec ular genetic and biochemical studies described here suggest that, as i n the case of growth factor receptors of higher eukaryotic cells, Ire1 p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by other Ire1p molecules as a r esult of oligomerization. In addition to its kinase domain, a C-termin al tail domain of Ire1p is required for induction of the UPR. The role of the tail is probably to bind other proteins that transmit the unfo lded protein signal to the nucleus.