Abstract
The endoplasmic reticulum (ER) is an important site for protein folding and maturation in eukaryotes. The cellular requirement to synthesize proteins within the ER is matched by its folding capacity. However, the physiological demands or aberrations in folding may result in an imbalance which can lead to the accumulation of misfolded protein, also known as “ER stress.” The unfolded protein response (UPR) is a cell-signaling system that readjusts ER folding capacity to restore protein homeostasis. The key UPR signal activator, IRE1, responds to stress by propagating the UPR signal from the ER to the cytosol. Here, we discuss the structural and molecular basis of IRE1 stress signaling, with particular focus on novel mechanistic advances. We draw a comparison between the recently proposed allosteric model for UPR induction and the role of Hsp70 during polypeptide import to the mitochondrial matrix.
Highlights
The endoplasmic reticulum is a major site for protein folding and maturation within the eukaryotic cell
For inositol requiring enzyme 1α/β (IRE1), this leads to the stimulation of endoribonuclease activity and the splicing of X-box-binding protein 1 (XBP1) mRNA to form a potent transcriptional activator, XBP1s (s refers to the spliced form) (Cox and Walter, 1996; Sidrauski and Walter, 1997; Calfon et al, 2002)
Great progress has been made toward understanding the mechanism of IRE1 stress signaling since its role was first described as mediating a rectifying signal that restores endoplasmic reticulum (ER) homeostasis
Summary
The endoplasmic reticulum is a major site for protein folding and maturation within the eukaryotic cell. Once in the ER, there are a number of glycosylating enzymes that either trim or add to the core N-linked oligosaccharide depending on the progress of protein folding These alterations to the glycan chain help to monitor the folding status of the nascent polypeptide and act as an important quality control measure (Wang and Kaufman, 2016; Hetz and Papa, 2017). A failure in the polypeptide chain to adopt its native conformation may lead to activation of degradation pathways, including ER-associated degradation (ERAD) (Hampton, 2002) In this process, misfolded protein is retro-translocated across the ER membrane into the cytosol, where it is ubiquitylated and targeted for degradation via the 26S proteasome. We discuss the molecular mechanisms that underlie this recognition process, and how this signal is propagated to the cytosol
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
