Regulation of Gene Expression and Cell Stress
The endoplasmic reticulum (ER) is the site where most transmembrane proteins are secreted and folded. When the folding capacity of the reticulum is compromised, this generates a situation known as ER stress, which is toxic to the cell. The unfolded protein response is the intracellular signaling pathway that makes it possible to communicate this situation to the cell nucleus, restore homeostasis of the ER and adjust the size of this organelle to the cell's needs.
A key step in the mechanisms of the UPR is the unconventional splicing of a single mRNA molecule which codes for transcription factor XBP1.This reaction takes place in the response centers to the ER stress, organized by the IRE1 stress sensor. Our previous research has shown the existence of a mechanism that allows mRNA to be transported from XBP1 to the centers; this mechanism is different from currently establish models. We are studying this and other new ways of targeting RNA at the ER membrane that may be of importance in biomedicine.
Splicing this mRNA permits the expression of the protein XBP1s, which activates a broad gene program. The transcriptional activity of XBP1s is broad and extends beyond controlling the folding ability of the ER, and affects the metabolism of sugars and lipids, and the life/death decisions that cells must make under conditions of prolonged or irresolvable stress. Our group studies the different mechanisms that XBP1s uses to activate different sets of genes and explores its importance in liver pathophysiology and in Parkinson's disease.