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Three UPR Transducers and One Master Regulator
- Signaling the Unfolded Protein Response from the Endoplasmic Reticulum

The basic components of the UPR pathway were first characterized in the budding yeast Saccharomyces cerevisiae in the early 1990s. The ER transmembrane protein kinase/endoribonuclease Ire1p/Ern1p was found to be essential for cell survival during ER stress and was identified as the transducer to initiate UPR signaling (5, 6). Thereafter, researchers found that all eukaryotic cells have conserved the essential and unique properties of Ire1p-mediated UPR signaling identified in yeast but also evolved additional transducers to generate a diversity of responses. In mammals, the counterpart of yeast Ire1p has two isoforms: IRE1a  and IRE1b. Whereas IRE1a is expressed in most cells and tissues, IRE1b expression is primarily restricted to the intestinal epithelial cells (7, 8). IRE1 contains an N-terminal ER stress-sensing domain in the ER lumen, an ER transmembrane domain, and a serine/threonine kinase domain and a C-terminal endoribonuclease domain in the cytosol (6, 9, 10) (Fig. 1). In addition to IRE1, higher eukaryotic cells have two additional UPR transducers: the double-stranded RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor 6 (ATF6). PERK contains a large ER luminal stress-sensing domain that is functionally interchangeable with the IRE1 luminal domain and a cytosolic domain that phosphorylates the a-subunit of eukaryotic translation initiation factor 2 (eIF2a) (1113). ATF6 is a transcription factor with an N-terminal basic leucine zipper (b-ZIP) domain in the cytosol and a C-terminal ER luminal domain to sense stress (14). Each UPR transducer is localized to the ER membrane and is constitutively expressed in all known metazoan cells.

Upon accumulation of unfolded proteins in the ER, the UPR is activated to reduce the amount of new proteins translocated into the ER lumen, to increase retrotranslocation and degradation of ER-localized proteins, and to bolster the protein-folding capacity and secretion potential of the ER. The UPR is orchestrated by transcriptional activation of multiple genes mediated by IRE1 and ATF6, a general decrease in translation initiation, and a selective translation of specific mRNAs mediated by PERK.

An essential unresolved issue for UPR signaling is how the different transducers are activated by a common stimulus, the accumulation of unfolded proteins in the ER lumen. Current studies support the fact that an ER chaperone protein, BiP (also known as GRP78), serves as a master UPR regulator and plays essential roles in activating IRE1, PERK, and ATF6 in response to ER stress (1517). BiP is a peptide-dependent ATPase and member of the heat shock 70 protein family that binds transiently to newly synthesized proteins translocated into the ER and more permanently to underglycosylated, misfolded, or unassembled proteins. Under non-stressed conditions, BiP also binds to the luminal domains of IRE1, PERK, and ATF6 to maintain them within the ER. Upon accumulation of unfolded proteins, BiP is released from IRE1 and PERK to permit their spontaneous dimerization/oligomerization, trans-autophosphorylation, and subsequent activation (16, 18). Release of ATF6 from BiP permits ATF6 transport to the Golgi compartment where it is cleaved to generate the cytosolic domain of ATF6 that translocates to the nucleus to activate transcription (17). Thus, this BiP-regulated activation provides a direct mechanism for all three UPR transducers to sense the "stress" in the ER and an autoregulatory mechanism by which the UPR is shut off upon increased expression of BiP (Fig. 1).

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