The UPRosome
How do cells sense protein folding stress? ER stress stimulates distinct stress sensors including IRE1, PERK and ATF6. IRE1 is part of the most conserved signalling branch of the UPR and harbors kinase and endoribonuclease (RNAse) activities within its cytosolic domain. IRE1 multimerization leads to the trans-autophosphorylation of its cytosolic domain, activating the RNAse domain. Active IRE1 processes the mRNA of X-Box binding protein-1 (XBP-1), shifting its codon reading frame with resultant expression of an active transcription factor (XBP-1s). XBP-1 mediates the upregulation of crucial UPR-related genes involved in folding, secretion, ER biogenesis, protein quality control and autophagy. Although PERK and IRE1 share functionally similar ER-luminal sensing domains and both are simultaneously activated in cellular paradigms of ER stress in vitro, they are selectively engaged in vivo by the physiological stress of unfolded proteins. The differences in terms of tissue-specific regulation of the UPR may be explained by the formation of distinct regulatory protein complexes. This concept is supported by the recent identification of adaptor and modulator proteins that directly interact with IRE1. We have identified a key role of the BCL-2 and Bax Iinhibitor-1 family of proteins in the control of the kinetics of IRE1 activation and inactivation. Our results support a model where IRE1 signaling emerges as a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, a complex referred to as the UPRosome.

ER STRESS in PHYSIOLOGY and DISEASE
ER stress is a hallmark feature of secretory cells and many diseases including cancer, neurodegeneration, and diabetes. Our laboratory is particularly committed to neurological diseases linked to abnormal protein misfolding, including, Prion disorders, Amyotrophic lateral sclerosis (ALS), Huntington’s Disease, Parkinson’s disease, in addition to Spinal Cord Injury.

Our central research questions are: