| Abstract: | ["The Unfolded Protein Response (UPR) is a pro-survival homeostatic response that enables cells to cope with endoplasmic reticulum (ER) stress. Yet, if ER homeostasis cannot be restored, the UPR transducers IRE1 and PERK turn pro-apoptotic. Inducible overexpression of the IgM heavy chain (\u00b5s) provokes a full-blown UPR in HeLa cells but no loss of cell viability, except upon ablation of the UPR transducer ATF6. Further ablation of IRE1 worsened cell fate, while reconstitution with GFP-tagged IRE1 expressed at near-endogenous levels restored viability. IRE1 signals ER-stress through the processing of XBP1 mRNA, such that it encodes a transcription factor that drives expression of ER components. Sustained IRE1 activation, however, leads to its RNase activity to be unleashed towards other mRNAs as well. We found that IRE1-GFP formed clusters during acute \u00b5s\u2013driven ER stress, but it relocalized diffusely throughout the ER under chronic \u00b5s\u2013driven ER stress. IRE1-GFP clusters persisted instead when ER homeostatic readjustment was unsuccessful, e.g. due to ATF6 ablation. I will present several lines of evidence, which indicate that life\/death decisions are taken through concentration of otherwise pro-survival IRE1 dimers into pro-apoptotic clusters, where IRE1 dimers are at a concentration that sustains cross-autophosphorylation and ensuing pro-apoptotic enhanced RNase activity."] |
