Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Jul 1;34(4):e00118.
doi: 10.1042/BSR20140058.

Endoplasmic Reticulum Stress Response in Yeast and Humans

Free PMC article

Endoplasmic Reticulum Stress Response in Yeast and Humans

Haoxi Wu et al. Biosci Rep. .
Free PMC article


Stress pathways monitor intracellular systems and deploy a range of regulatory mechanisms in response to stress. One of the best-characterized pathways, the UPR (unfolded protein response), is an intracellular signal transduction pathway that monitors ER (endoplasmic reticulum) homoeostasis. Its activation is required to alleviate the effects of ER stress and is highly conserved from yeast to human. Although metazoans have three UPR outputs, yeast cells rely exclusively on the Ire1 (inositol-requiring enzyme-1) pathway, which is conserved in all Eukaryotes. In general, the UPR program activates hundreds of genes to alleviate ER stress but it can lead to apoptosis if the system fails to restore homoeostasis. In this review, we summarize the major advances in understanding the response to ER stress in Sc (Saccharomyces cerevisiae), Sp (Schizosaccharomyces pombe) and humans. The contribution of solved protein structures to a better understanding of the UPR pathway is discussed. Finally, we cover the interplay of ER stress in the development of diseases.


Figure 1
Figure 1. Activation of the UPR
ER stress transducer, Ire1α, PERK and ATF6 form the three branches of the UPR pathways in mammals. In response to ER stress, the release of the molecular chaperone BiP, from the lumenal domain of Ire1α, promotes binding of misfolded proteins. Subsequently, Ire1α oligomerizes and phosphorylates itself, splices XBP1 mRNA and this results in the translation of the transcription factor XBP1 regulating downstream signalling cascade. Upon prolonged ER stress, Ire1α cleaves mRNAs to relieve protein load through its RIDD activity. PERK oligomerizes and phosphorylates itself together with eIF2α, where it attenuates protein translation. It further activates the transcription factor ATF4, which carries out downstream activation of UPR genes. Under ER stress, ATF6 is packaged into vesicles and transported to the Golgi apparatus. Cleavage of ATF6 lumenal and transmembrane domain occur, where the N-terminal cytosolic fragment, ATF6(N) localize into the nucleus to activate UPR target genes.
Figure 2
Figure 2. UPR in yeast
(A) S. cerevisiae Ire1 is activated by ER stress. Upon activation, Ire1 undergoes trans-autophosphorylation and oligomerization. HAC1 mRNA is spliced by activated Ire1 through its RNase domain. Upon translation, transcription factor Hac1 up-regulates UPR target genes to restore homoeostasis. (B) In S. pombe upon ER stress, Ire1 triggers downstream RIDD; the protein BiP1′s poly-A tail is recognized and cleaved by RIDD, but BiP1 protein is stabilized despite the cleavage of its mRNA. BiP1 protein is important for cell survival during stress condition; there are possible unknown candidates also involved in stress response, either in ER lumen or on ER membrane.
Figure 3
Figure 3. Solved protein structures of the UPR activation pathway
(A) Schematic representation of yeast Ire1, human Ire1α and mouse PERK proteins. Ss (Signal sequence), TM (transmembrane domain), KEN domain. (B) Ribbons representation of dimerized cLD (amino acids 111–449) of Sc (S. cerevisiae) Ire1 [PDB (Protein Data Bank) code: 2BE1]. (C) Ribbons representation of the dimerized cytosolic domain of Sc Ire1 (PDB code: 3FBV). (D) Ribbons representation of human Ire1α luminal domain. The dimer adapts a back to back orientation (PDB code: 2HZ6). (E) Ribbons representation of PERK protein kinase domain from mouse (PDB code: 3QD2). All structures were drawn using PyMOL (
Figure 4
Figure 4. Diseases linked to ER stress
During ER stress, misfolded proteins arising in the ER is assisted with chaperones for refolding, and failure to be refolded to their native state would result in their degradation via the ERAD pathway. The UPR is activated with the accumulation of unfolded or misfolded proteins, which would then halt protein translation and induce stress-response genes. Under prolonged ER stress, apoptosis is initiated by the UPR. Diseased states often arise from the failure of the UPR to respond well under ER stress, or from an accumulation of unfolded proteins. Inadequate response of the UPR could result when elements in the UPR signalling cascade is down-regulated and hence, a sufficient response could not be mounted to alleviate ER stress. Diseases such as NAFLD, T2D (type II diabetes) and cancer are implicated in this model. Mutations in protein coding genes could cause proteins synthesized to be misfolded and form aggregates rapidly. This could be severe that the ERAD fails to degrade the proteins adequately and the UPR is unable to compensate for the ER stress. This model often includes degenerative diseases such as PD, HD and AD.

Similar articles

See all similar articles

Cited by 27 articles

See all "Cited by" articles


    1. Kozutsumi Y., Segal M., Normington K., Gething M. J., Sambrook J. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature. 1988;332:462–464. doi: 10.1038/332462a0. - DOI - PubMed
    1. Dorner A. J., Wasley L. C., Raney P., Haugejorden S., Green M., Kaufman R. J. The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion. J. Biol. Chem. 1990;265:22029–22034. - PubMed
    1. Cox J. S., Shamu C. E., Walter P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell. 1993;73:1197–1206. doi: 10.1016/0092-8674(93)90648-A. - DOI - PubMed
    1. Mori K., Ma W., Gething M. J., Sambrook J. A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus. Cell. 1993;74:743–756. doi: 10.1016/0092-8674(93)90521-Q. - DOI - PubMed
    1. Cox J. S., Walter P. A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell. 1996;87:391–404. doi: 10.1016/S0092-8674(00)81360-4. - DOI - PubMed

Publication types

MeSH terms