Project: A new IRE-1 dependent pathway in ER stress involving TAOK3
01/01/11 – 31/12/14
The endoplasmic reticulum (ER) is responsible for the correct folding of newly formed proteins and their posttranscriptional modification. Unproperly folded proteins accumulate in the ER, consume chaperone molecules and lead to activation of 3 ER stress sensors: ATF6, PERK and IRE1. IRE1 is the most conserve sensor and has 2 catalytic functions: a trans-activating kinase activity and an endonuclease domain resulting in XBP1 activation. XBP1 is traditionally seens as the downstream transcription factor that causes the induction of genes that increase protein folding and restore homeostasis in the ER. Recent findings however suggest that IRE1 also leads to activation of MAP kinases like JNK, possibly linking ER stress to inflammation, autophagy and apoptosis. In this project, we will further explore the molecular biology of this pathway extensively, focusing on TAOK3 (thousand and one kinase 3, a kinase linking IRE1 to JNK activation) and uravel why deficiency of this kinase has profound effects on cells of the immune system.