Get The IRE1-XBP1 Pathway Of The Unfolded Protein Response Is Required For Adipogenesis - Human Cornell

The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins.

The IRE1 pathway is the most evolutionarily conserved arm of the UPR, as it is found in all eukaryotes from yeast to mammals12. In response to ER stress, IRE1 is activated through a mechanism involving autophosphorylation, oligomerization and allosteric activation of a cytosolic endoribonuclease (RNAse) domain13,14,15.

The UPR is activated when unfolded proteins accumulate in the endoplasmic reticulum. This accumulation puts a greater load on the molecules in charge of folding the proteins, and therefore the UPR works to balance this by lowering the number of unfolded proteins present in the cell.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation.

Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress.

XBP1 acts to regulate endothelial cell proliferation through growth factor pathways, leading to angiogenesis. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with HDAC3.

This signalling pathway is known as the unfolded protein response (UPR). The UPR detects the build-up of unfolded or misfolded proteins and adjust the protein folding ability of the ER.

Like PERK, IRE1 is capable of inducing cell fate by two distinct routes: The first by induction of adaptive cellular response by unconventional splicing of the transcription factor X-box binding protein 1 (XBP1) mRNA or Regulated IRE1-Dependent Decay (RIDD) posttranscriptional modifications, and the second by ...

Cells operate a signaling network termed unfolded protein response (UPR) to monitor protein-folding capacity in the endoplasmic reticulum (ER). IRE1 is an ER transmembrane sensor that activates UPR to maintain ER and cellular function.

Unspliced XBP1 mRNA is converted to spliced XBP1 mRNA by IRE1-mediated unconventional splicing in response to ER stress (Figure 6B). Activated IRE1 thus cleaves unspliced XBP1 mRNA at two characteristic stem-7-nucleotide-loop structures as shown in Figure 6Ea.

The XBP1 mRNA encodes for a non-functional protein that is activated via an IRE1-dependent unconventional cytosolic mRNA splicing event that generates a mature XBP1 protein (XBP1s) harboring a potent transactivation domain.

X-box binding protein 1 (XBP1) is a unique basic region leucine zipper (bZIP) transcription factor whose active form is generated by a nonconventional splicing reaction upon disruption of homeostasis in the endoplasmic reticulum (ER) and activation of the unfolded protein response (UPR).