Unfolded Protein Response (Homo sapiens)

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1-59, 10, 25, 276, 20, 2135-4021, 2235, 3617-196, 20, 2112, 28, 329, 25, 268-1028-317, 22-2417-1911-13, 33, 3435, 3641, 4214-16, 42-46endoplasmic reticulum lumencytosolmitochondrial matrixGolgi lumenclathrin sculpted glutamate transport vesiclelysosomal lumennucleoplasmIRE1 homodimer (phosphorylated)PERKAcyl-CoA dehydrogenase, very-long-chain specific, mitochondrial precursorPERK:BiP HeterodimerBiP:unfolded protein complexProteins Upregulated by ATF4Proteins Upregulated by XBP1(S)unfolded proteinPERK HomodimerATF6-alphaeIF2-alpha (phosphorylated at Ser52)Proteins Upregulated by ATF6-alphaIRE1 homodimer (phosphorylated):ADPS1PATF6-alpha, C-terminal cleavage product of S1PNF-YS2PNF-YAProteins Upregulated by XBP1(S)ADPATPIRE1 homodimerProteins Upregulated by XBP1(S)ATF4ATF6-alpha, N-terminal cleavage product of S1PXbp1 mRNA (spliced)eIF2-alphaATF6-alpha, C-terminal cleavage product of S2PAsparagine synthetaseATPIRE1:BiP ComplexXBP1(S)Vacuolar ATPase subunit D1IRE1Tripeptidyl-peptidase 1ATF6-alphaProteins Upregulated by XBP1(S)ATF6-alpha, N-terminal cleavage product of S2PADPProteins Upregulated by ATF6-alphaXbp1 mRNA (unspliced)ATF6-alpha:BiP ComplexCyclic AMP-dependent transcription factor ATF-3ATF6-alpha, N-terminal cleavage product of S2PProteins Upregulated by ATF48-1011-131177614-161168-1011


Description

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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Bibliography

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History

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CompareRevisionActionTimeUserComment
123614view08:19, 7 August 2022EgonwModified title
114872view16:38, 25 January 2021ReactomeTeamReactome version 75
113318view11:38, 2 November 2020ReactomeTeamReactome version 74
112529view15:49, 9 October 2020ReactomeTeamReactome version 73
101441view11:31, 1 November 2018ReactomeTeamreactome version 66
100979view21:09, 31 October 2018ReactomeTeamreactome version 65
100515view19:43, 31 October 2018ReactomeTeamreactome version 64
100061view16:26, 31 October 2018ReactomeTeamreactome version 63
99613view15:00, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99222view12:44, 31 October 2018ReactomeTeamreactome version 62
93967view13:48, 16 August 2017ReactomeTeamreactome version 61
93565view11:27, 9 August 2017ReactomeTeamreactome version 61
86666view09:23, 11 July 2016ReactomeTeamreactome version 56
83168view10:15, 18 November 2015ReactomeTeamVersion54
81749view09:49, 26 August 2015ReactomeTeamVersion53
77024view08:32, 17 July 2014ReactomeTeamFixed remaining interactions
76729view12:09, 16 July 2014ReactomeTeamFixed remaining interactions
76054view10:11, 11 June 2014ReactomeTeamRe-fixing comment source
75764view11:27, 10 June 2014ReactomeTeamReactome 48 Update
75114view14:06, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74761view08:50, 30 April 2014ReactomeTeamReactome46
45018view18:38, 6 October 2011KhanspersOntology Term : 'ER stress - UPR pathway' added !
42154view22:01, 4 March 2011MaintBotAutomatic update
39965view05:58, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
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)
ATF6-alpha:BiP

Complex

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)
Acyl-CoA

dehydrogenase, very- long-chain specific, mitochondrial precursor

ProteinP49748 (UniProt)
Asparagine

synthetase

ProteinP08243 (UniProt)
BiP:unfolded

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)
IRE1

homodimer

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

(phosphorylated)

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.
IRE1:BiP

Complex

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)
PERK

Homodimer

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

Heterodimer

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

Upregulated by ATF4

ProteinREACT_22949 (Reactome)
Proteins

Upregulated by XBP1(S)

ProteinREACT_22515 (Reactome)
Proteins

Upregulated by ATF4

ProteinREACT_19023 (Reactome)
Proteins

Upregulated by ATF6-alpha

ProteinREACT_25879 (Reactome)
Proteins

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.
Proteins

Upregulated by XBP1(S)

ProteinREACT_22446 (Reactome)
Proteins

Upregulated by XBP1(S)

ProteinREACT_22840 (Reactome)
Proteins Upregulated

by ATF6-alpha

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

peptidase 1

ProteinO14773 (UniProt)
Vacuolar

ATPase subunit D1

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

(spliced)

RnaENST00000344347 (ENSEMBL)
Xbp1 mRNA

(unspliced)

RnaENST00000216037 (ENSEMBL)
eIF2-alpha ProteinP05198 (UniProt)
eIF2-alpha

(phosphorylated at Ser52)

ProteinP05198 (UniProt)
unfolded

protein

UnknownREACT_18756 (Reactome)

Annotated Interactions

No annotated interactions

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