Unfolded Protein Response (UPR) (Homo sapiens)

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1-541, 4214-16, 42-4611-13, 33, 3417-1935, 366, 20, 2121, 2228-319, 10, 25, 2735, 3617-196, 20, 217, 22-249, 25, 268-1012, 28, 3235-40lysosomal lumenGolgi lumennucleoplasmendoplasmic reticulum lumenclathrin sculpted glutamate transport vesiclecytosolmitochondrial matrixPERK HomodimerATF6-alphaBiP:unfolded protein complexATF6-alpha:BiP ComplexXbp1 mRNA (spliced)Xbp1 mRNA (unspliced)IRE1 homodimer (phosphorylated)ATF6-alpha, N-terminal cleavage product of S2PPERK:BiP HeterodimerProteins Upregulated by XBP1(S)PERKATF6-alpha, N-terminal cleavage product of S1PIRE1Proteins Upregulated by ATF6-alphaProteins Upregulated by XBP1(S)unfolded proteinProteins Upregulated by ATF4XBP1(S)S1PATF6-alphaADPATPAsparagine synthetaseADPTripeptidyl-peptidase 1ATF6-alpha, C-terminal cleavage product of S1PProteins Upregulated by XBP1(S)Proteins Upregulated by ATF6-alphaAcyl-CoA dehydrogenase, very-long-chain specific, mitochondrial precursorATF6-alpha, C-terminal cleavage product of S2PATPATF6-alpha, N-terminal cleavage product of S2PVacuolar ATPase subunit D1IRE1 homodimer (phosphorylated):ADPeIF2-alpha (phosphorylated at Ser52)NF-YATF4Proteins Upregulated by XBP1(S)IRE1 homodimerS2PNF-YAProteins Upregulated by ATF4Cyclic AMP-dependent transcription factor ATF-3eIF2-alphaIRE1:BiP Complex1178-10611-1314-166711118-10


The Unfolded Protein Response (UPR) is a regulatory system that protects the Endoplasmic Reticulum (ER) from overload. The UPR is provoked by the accumulation of improperly folded protein in the ER during times of unusually high secretion activity. Analysis of mutants with altered UPR, however, shows that the UPR is also required for normal development and function of secretory cells.
One level at which the URP operates is transcriptional and translational regulation: mobilization of ATF6 and IRE1 leads to increased transcription of genes encoding chaperones, and mobilization of PERK (pancreatic eIF2alpha kinase) leads to phosphorylation of the translation initiation factor eIF2alpha and global down-regulation of protein synthesis. These three regulatory pathways are annotated here.

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  44. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K.; ''XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.''; PubMed Europe PMC Scholia
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  65. Gargalovic PS, Imura M, Zhang B, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Patel S, Nelson SF, Horvath S, Berliner JA, Kirchgessner TG, Lusis AJ.; ''Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.''; PubMed Europe PMC Scholia
  66. Liang G, Yang J, Wang Z, Li Q, Tang Y, Chen XZ.; ''Polycystin-2 down-regulates cell proliferation via promoting PERK-dependent phosphorylation of eIF2alpha.''; PubMed Europe PMC Scholia
  67. Kakiuchi C, Ishiwata M, Hayashi A, Kato T.; ''XBP1 induces WFS1 through an endoplasmic reticulum stress response element-like motif in SH-SY5Y cells.''; PubMed Europe PMC Scholia
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External references


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NameTypeDatabase referenceComment
ADP Metabolite16761 (ChEBI)
ATF4 ProteinP18848 (UniProt)
ATF6-alpha ProteinP18850 (UniProt)
ATF6-alpha, C-

terminal cleavage product of S2P

ProteinP18850 (UniProt)
ATF6-alpha, C-terminal

cleavage product of S1P

ProteinP18850 (UniProt)
ATF6-alpha, N-

terminal cleavage product of S2P

ProteinP18850 (UniProt)
ATF6-alpha, N-terminal

cleavage product of S1P

ProteinP18850 (UniProt)


ComplexREACT_18758 (Reactome) The luminal C-terminus of ATF6-alpha binds BiP, occluding two Golgi Localization Sequences and causing ATF6-alpha to be retained in the endoplasmic reticulum.
ATP Metabolite15422 (ChEBI)

dehydrogenase, very- long-chain specific, mitochondrial precursor

ProteinP49748 (UniProt)


ProteinP08243 (UniProt)

protein complex

ComplexREACT_18551 (Reactome) BiP is a chaperone which binds unfolded proteins as well as the luminal domains of UPR signal transducers ATF6, IRE1, and PERK.
Cyclic AMP-dependent

transcription factor ATF-3

ProteinP18847 (UniProt)
IRE1 ProteinO75460 (UniProt)


ComplexREACT_18870 (Reactome) Crystallographic evidence indicates that the IRE1 homodimer forms by an initial interaction between the luminal N-terminal domains of IRE1 monomers.
IRE1 homodimer


ComplexREACT_19024 (Reactome) After juxtaposition of the luminal N-termini of IRE1 to form the IRE1 homodimer, the cytoplasmic C-terminal kinase domains of the IRE1 molecules associate and transphosphorylate each other's A-loop domains. This causes a change in conformation that allows binding of ADP.
IRE1 homodimer

(phosphorylated): ADP

ComplexREACT_18755 (Reactome) Phosphorylated IRE1 homodimers preferentially bind ADP (as opposed to ATP) and this binding promotes association of the cytoplasmic C-termini. Crystallographic evidence indicates that unphosphorylated A-loops of IRE1 interfere with nucleotide binding thus trans-autophosphorylation is a prerequisite to nucleotide binding.


ComplexREACT_18771 (Reactome) The luminal N-teminal domain of IRE1 binds the ATPase domain of BiP, rendering IRE1 inactive.
NF-Y ComplexREACT_26721 (Reactome) NF-Y is a ubiquitous heterotrimeric transcription factor comprising subunits NF-Y A, NF-Y B, and NF-Y C. It binds the sequence CCAAT.
NF-YA ProteinP23511 (UniProt)
PERK ProteinQ9NZJ5 (UniProt)


ComplexREACT_18942 (Reactome) PERK monomers form dimers, resulting in activation of the kinase activity of the cytosolic C-terminal region.


ComplexREACT_18951 (Reactome) The N-terminal luminal domain of PERK binds BiP, rendering PERK inactive.

Upregulated by ATF4

ProteinREACT_22949 (Reactome)

Upregulated by XBP1(S)

ProteinREACT_22515 (Reactome)

Upregulated by ATF4

ProteinREACT_19023 (Reactome)

Upregulated by ATF6-alpha

ProteinREACT_25879 (Reactome)

Upregulated by XBP1(S)

ProteinREACT_18474 (Reactome) Members of this set have been demonstrated to be upregulated by the transcription factor XBP1(S) in humans. Candidate members of this set are inferred from experimental results in mice.

Upregulated by XBP1(S)

ProteinREACT_22446 (Reactome)

Upregulated by XBP1(S)

ProteinREACT_22840 (Reactome)
Proteins Upregulated

by ATF6-alpha

ProteinREACT_19002 (Reactome)
S1P ProteinQ14703 (UniProt)
S2P ProteinO43462 (UniProt)

peptidase 1

ProteinO14773 (UniProt)

ATPase subunit D1

ProteinP61421 (UniProt)
XBP1(S) ProteinP17861-2 (UniProt)
Xbp1 mRNA


RnaENST00000344347 (ENSEMBL)
Xbp1 mRNA


RnaENST00000216037 (ENSEMBL)
eIF2-alpha ProteinP05198 (UniProt)

(phosphorylated at Ser52)

ProteinP05198 (UniProt)


UnknownREACT_18756 (Reactome)

Annotated Interactions

No annotated interactions

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