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New insights Into unconventional splicing and modulation of RNase activities of IRE1, a multifunctional UPR component


The endoplasmic reticulum (ER) is an important organelle where secreted and membrane proteins are initially folded and processed properly. Professional secretory cells are especially sensitive to changes in ER folding need and must respond by adjusting ER folding capacity for proper secretion. The Unfolded Protein Response is a pathway that senses changes in ER requirement and increases ER function appropriately mainly by activation of several transcription factors which upregulate genes such as ER chaperones which increase ER folding capacity. However, if the distress in the ER cannot be solved, then the UPR can also activate cell death pathways. IRE1 is an ER transmembrane protein and is the most evolutionarily conserved branch of the UPR, present from yeast to humans. It is a multifunctional protein containing a cytosolic domain with both kinase and nuclease functions. Its kinase function has been implicated in activation of cellular pathways such as JNK, while its nuclease is involved in unconventional splicing of an mRNA coding for a transcription factor. Splicing of this mRNA is a key event in activation of this UPR transcription factor. Here we show new insights into IRE1's functions and roles in the cell. We show that IRE1 is required for full activation of NF-[kappa]B, a transcription factor. Furthermore, IRE1 dependent NF-[kappa]B activation is required for full activation of a subset of UPR target genes, making it an integral part of the UPR. Also, we show that IRE1 is able to differentially recognize splice sites of its substrates, giving us increased understating of IRE1's unconventional splicing ability. Finally, we show direct evidence that IRE1 is able to cleave ER localized mRNAs, indicating an alternate activation mode for IRE1's nuclease. We also demonstrate that we are able to pharmacologically manipulate IRE1's nuclease modes which may be useful in targeting IRE1 related diseases

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