Unfolded Protein Response (Homo sapiens)

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14, 20, 22, 23, 3515, 19, 367, 17, 441, 42, 34, 3715, 19, 361, 47, 17, 441, 4, 26, 30, 31, 426, 10, 3715, 2711, 292, 6, 8, 3712, 41, 4513, 16, 32, 45cytosolnucleoplasmGolgi lumenendoplasmic reticulum lumenMBTPS2ADP p-S724-IRE1 dimerunfolded proteinp-S724-ERN1 EIF2AK3 ATF4 activates genesADPXbp1 mRNA(unspliced)PERK:BiPATF6IRE1:BiPATF4 mRNAHSPA5 ATF6-alpha:BiPp-S52-EIF2S1HSPA5 ATF6(420-670)p-S724-IRE1dimer:ADPATF6(1-379)XBP1-2ATF6(380-419)IRE1 dimerHSPA5 ATF6 ERN1 Xbp1 mRNA (spliced)BiP:Unfolded ProteinEIF2S1ATF6(1-379)ATF6(1-419)ERN1ERN1 MBTPS1p-S724-ERN1 ATPATF6EIF2AK3 ATPXBP1(S) activateschaperone genesADPHSPA5 ATF4PERK dimerunfolded protein ATF6-alpha activateschaperone genesEIF2AK32, 34, 37362, 34, 373, 18, 24, 29, 33...5, 12, 28, 38, 392, 34, 372, 34, 37369, 21, 25, 27


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, EIF2AK3) leads to phosphorylation of the translation initiation factor eIF2alpha and global down-regulation of protein synthesis. These three regulatory pathways are annotated here. View original pathway at:Reactome.

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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 MetaboliteCHEBI:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATF4 activates genesPathwayR-HSA-380994 (Reactome) ATF4 is a transcription factor and activates expression of IL-8, MCP1, IGFBP-1, CHOP, HERP1 and ATF3.
ATF4 mRNARnaENST00000404241 (Ensembl)
ATF4ProteinP18848 (Uniprot-TrEMBL)
ATF6 ProteinP18850 (Uniprot-TrEMBL)
ATF6(1-379)ProteinP18850 (Uniprot-TrEMBL)
ATF6(1-419)ProteinP18850 (Uniprot-TrEMBL)
ATF6(380-419)ProteinP18850 (Uniprot-TrEMBL)
ATF6(420-670)ProteinP18850 (Uniprot-TrEMBL)
ATF6-alpha activates chaperone genesPathwayR-HSA-381183 (Reactome) The N-terminal fragment of ATF6-alpha contains a bZIP domain and binds the sequence CCACG in ER Stress Response Elements (ERSEs). ATF6-alpha binds ERSEs together with the heterotrimeric transcription factor NF-Y, which binds the sequence CCAAT in the ERSEs, and together the two factors activate transcription of ER stress-responsive genes. Evidence from overexpression and knockdowns indicates that ATF6-alpha is a potent activator but its homolog ATF6-beta is not and ATF6-beta may actually reduce expression of ER stress proteins.
ATF6-alpha:BiPComplexR-HSA-381168 (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.
ATF6ProteinP18850 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BiP:Unfolded ProteinComplexR-HSA-381062 (Reactome) BiP is a chaperone which binds unfolded proteins as well as the luminal domains of UPR signal transducers ATF6, IRE1, and PERK (EIF2AK3).
EIF2AK3 ProteinQ9NZJ5 (Uniprot-TrEMBL)
EIF2AK3ProteinQ9NZJ5 (Uniprot-TrEMBL)
EIF2S1ProteinP05198 (Uniprot-TrEMBL)
ERN1 ProteinO75460 (Uniprot-TrEMBL)
ERN1ProteinO75460 (Uniprot-TrEMBL)
HSPA5 ProteinP11021 (Uniprot-TrEMBL)
IRE1 dimerComplexR-HSA-381200 (Reactome) Crystallographic evidence indicates that the IRE1 homodimer forms by an initial interaction between the luminal N-terminal domains of IRE1 monomers.
IRE1:BiPComplexR-HSA-381202 (Reactome) The luminal N-teminal domain of IRE1 binds the ATPase domain of BiP, rendering IRE1 inactive.
MBTPS1ProteinQ14703 (Uniprot-TrEMBL)
MBTPS2ProteinO43462 (Uniprot-TrEMBL)
PERK dimerComplexR-HSA-381126 (Reactome) PERK (EIF2AK3) monomers form dimers, resulting in activation of the kinase activity of the cytosolic C-terminal region.
PERK:BiPComplexR-HSA-381216 (Reactome) The N-terminal luminal domain of PERK (EIF2AK3) binds BiP, rendering PERK inactive.
XBP1(S) activates chaperone genesPathwayR-HSA-381038 (Reactome) Xbp-1 (S) binds the sequence CCACG in ER Stress Responsive Elements (ERSE, consensus sequence CCAAT (N)9 CCACG) located upstream from many genes. The ubiquitous transcription factor NF-Y, a heterotrimer, binds the CCAAT portion of the ERSE and together the IRE1-alpha: NF-Y complex activates transcription of a set of chaperone genes including DNAJB9, EDEM, RAMP4, p58IPK, and others. This results in an increase in protein folding activity in the ER.
XBP1-2ProteinP17861-2 (Uniprot-TrEMBL)
Xbp1 mRNA (unspliced)RnaENST00000216037 (Ensembl)
Xbp1 mRNA (spliced)RnaENST00000344347 (Ensembl)
p-S52-EIF2S1ProteinP05198 (Uniprot-TrEMBL)
p-S724-ERN1 ProteinO75460 (Uniprot-TrEMBL) IRE1 is trans-autophosphorylated after dissociation from BiP and autodimerization. By homology with the yeast IRE1, human IRE1 is believed to be phosphorylated at Ser724 (Ser841 of Saccharomyces cerevisiae)
p-S724-IRE1 dimer:ADPComplexR-HSA-381078 (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.
p-S724-IRE1 dimerComplexR-HSA-381154 (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.
unfolded protein R-HSA-381130 (Reactome)
unfolded proteinR-HSA-381130 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-381091 (Reactome)
ADPArrowR-HSA-381111 (Reactome)
ADPR-HSA-381116 (Reactome)
ATF4 mRNAR-HSA-381128 (Reactome)
ATF4ArrowR-HSA-381128 (Reactome)
ATF6(1-379)ArrowR-HSA-381026 (Reactome)
ATF6(1-379)ArrowR-HSA-420818 (Reactome)
ATF6(1-379)R-HSA-381026 (Reactome)
ATF6(1-419)ArrowR-HSA-381135 (Reactome)
ATF6(1-419)R-HSA-420818 (Reactome)
ATF6(380-419)ArrowR-HSA-420818 (Reactome)
ATF6(420-670)ArrowR-HSA-381135 (Reactome)
ATF6-alpha:BiPR-HSA-381158 (Reactome)
ATF6ArrowR-HSA-381158 (Reactome)
ATF6ArrowR-HSA-381186 (Reactome)
ATF6R-HSA-381135 (Reactome)
ATF6R-HSA-381186 (Reactome)
ATPR-HSA-381091 (Reactome)
ATPR-HSA-381111 (Reactome)
BiP:Unfolded ProteinArrowR-HSA-381086 (Reactome)
BiP:Unfolded ProteinArrowR-HSA-381158 (Reactome)
BiP:Unfolded ProteinArrowR-HSA-381217 (Reactome)
EIF2AK3ArrowR-HSA-381086 (Reactome)
EIF2AK3R-HSA-381087 (Reactome)
EIF2S1R-HSA-381111 (Reactome)
ERN1ArrowR-HSA-381217 (Reactome)
ERN1R-HSA-381109 (Reactome)
IRE1 dimerArrowR-HSA-381109 (Reactome)
IRE1 dimerR-HSA-381091 (Reactome)
IRE1 dimermim-catalysisR-HSA-381091 (Reactome)
IRE1:BiPR-HSA-381217 (Reactome)
MBTPS1mim-catalysisR-HSA-381135 (Reactome)
MBTPS2mim-catalysisR-HSA-420818 (Reactome)
PERK dimerArrowR-HSA-381087 (Reactome)
PERK dimermim-catalysisR-HSA-381111 (Reactome)
PERK:BiPR-HSA-381086 (Reactome)
R-HSA-381026 (Reactome) The cytosolic N-terminal cleavage product of ATF6-alpha transits to the nucleus.
R-HSA-381086 (Reactome) PERK (EIF2AK3) is a single-pass transmembrane protein located in the Endoplasmic Reticulum (ER) membrane. PERK has an N-terminal luminal domain and a C-terminal cytosolic domain. It is maintained in an inactive state by association of its luminal domain with BiP, a chaperone in the ER. Because BiP also binds unfolded proteins, BiP dissociates from PERK when unfolded proteins exceed chaperone activity in the ER.
R-HSA-381087 (Reactome) Once dissociated from BiP, PERK (EIF2AK3) monomers form homodimers, the active form of the protein.
R-HSA-381091 (Reactome) Dimerization of the N-terminal luminal regions of IRE1-alpha brings the cytosolic C-terminal regions in proximity. The C-terminal region possesses kinase activity and the homodimer trans-autophosphorylates. From homology with Saccharomyces IRE1-alpha the phosphorylation of human IRE1-alpha is believed to be at Ser724.
R-HSA-381109 (Reactome) The dissociation of the IRE1-alpha:BiP heterodimer liberates IRE1-alpha, which forms homodimers. Dimer formation is initiated by interaction between the N-terminal, luminal domains.
R-HSA-381111 (Reactome) The C-terminal domain of PERK (EIF2AK3) has kinase activity when PERK homodimerizes. PERK kinase specifically phosphorylates Ser52 of eIF2-alpha, causing an arrest in translation. The result is that translation of ER-targeted proteins is halted on ribosomes in the vicinity of activated PERK. The general arrest of translation results in the loss of short-lived proteins such as Cyclin D1, causing an arrest of the cell cycle in G1.
R-HSA-381116 (Reactome) Phosphorylation of the C-terminal region causes a loop in the C-terminus to change position, enabling access to an ADP-binding pocket. Phosphorylated IRE1-alpha dimers bind ADP in preference to ATP.
R-HSA-381128 (Reactome) Phosphorylation of eIF2-alpha causes increased translation of ATF4 mRNA. In mouse the mRNA of ATF4 contains 2 upstream ORFs (uORFs) (Vattem and Wek 2004). The second uORF overlaps the ORF encoding ATF4 and thus prevents translation of ATF4. When eIF2-alpha is phosphorylated, translation of the uORFs is suppressed and translation of the ORF encoding ATF4 is increased.
R-HSA-381135 (Reactome) Once in the Golgi, ATF6-alpha undergoes two sequential proteolytic cleavages. S1P catalyzes the first of these, probably cleaving the ATF6-alpha polypeptide between residues 418 and 419 based on homology with known S1P cleavage sites in other proteins.
R-HSA-381158 (Reactome) ATF6-alpha is a transmembrane protein located in the endoplasmic reticulum (ER) membrane with N-terminal cytoplasmic and C-terminal luminal domains. BiP binds the luminal domain of ATF6-alpha via the substrate binding domain of BiP. Binding of BiP blocks 2 Golgi localization sequences on ATF6-alpha, maintaining ATF6-alpha in the ER.
BiP is also a general chaperone capable of binding unfolded proteins in the ER lumen. When chaperone activity in the ER is overwhelmed, BiP dissociates from ATF6-alpha and binds the excess unfolded proteins. It is unclear whether the dissociation is due to competition of unfolded proteins for BiP or to a more specific interaction between BiP and ATF6-alpha. The dissociation exposes the Golgi localization sequences of ATF6-alpha and allows ATF6-alpha to transit to the Golgi.
R-HSA-381186 (Reactome) The association between ATF6-alpha and BiP causes ATF6-alpha to be retained in the endoplasmic reticulum (ER). Once dissociated from BiP, the 2 Golgi Localization Sequences on ATF6-alpha are exposed and ATF6-alpha transits from the ER to the Golgi Apparatus.
R-HSA-381203 (Reactome) Phosphorylated IRE1-alpha homodimers with bound ADP have endoribonuclease activity in their C-terminal (cytosolic) regions. In particular, the homodimers cleave an internal 26 nucleotide segment out of the Xbp-1 mRNA. In yeast the resulting RNAs are ligated by a tRNA ligase but the corresponding human enzyme has not been identified. The cleavage and ligation leads to a frameshift which results in a longer ORF that encodes Xbp-1 (S), the active form of the Xbp-1 transcription factor.
The ribonuclease activity of IRE1-alpha also degrades subsets of mRNAs in the vicinity of the ER membrane, thereby reducing the amount of protein entering the ER.
Xbp-1 mRNA that has been cleaved by IRE1-alpha encodes a 40 kd protein designated Xbp-1 (S). Xbp-1 (S) is a potent bZIP transcription factor that transits from the cytosol to the nucleus and binds the sequence CCACG in the ER Stress Responsive Element (ERSE).
R-HSA-381217 (Reactome) IRE1-alpha is a single-pass transmembrane protein with a luminal N-terminus and a cytoplasmic C-terminus. IRE1-alpha is maintained in an inactive state in the Endoplasmic Reticulum (ER) membrane by interaction between the luminal domain of IRE1-alpha and the ATPase domain of BiP within the ER.
BiP is a general chaperone that also binds unfolded proteins within the ER. Thus BiP dissociates from IRE1-alpha when chaperone activity is overwhelmed by unfolded proteins in the ER.
R-HSA-420818 (Reactome) Once in the Golgi, ATF6-alpha undergoes two sequential proteolytic cleavages. S2P catalyzes the second of these, cleaving the ATF6-alpha S1P cleavage product within its transmembrane domain. This cleavage liberates a 50 kD N-terminal fragment with bZIP transcription factor activity into the cytosol.
R-HSA-425923 (Reactome) Phosphorylated IRE1-alpha homodimers with bound ADP have endoribonuclease activity in their C-terminal (cytosolic) regions. The IRE1-alpha homodimers cleave an internal 26 nucleotide segment out of the Xbp-1 mRNA. In yeast the resulting RNAs are ligated by a tRNA ligase but the corresponding human ligase has not been identified. The cleavage and ligation leads to a frameshift in the Xbp-1 mRNA which results in a longer ORF that encodes Xbp-1 (S), the active form of the Xbp-1 transcription factor
XBP1-2ArrowR-HSA-381203 (Reactome)
Xbp1 mRNA (unspliced)R-HSA-425923 (Reactome)
Xbp1 mRNA (spliced)ArrowR-HSA-425923 (Reactome)
Xbp1 mRNA (spliced)R-HSA-381203 (Reactome)
p-S52-EIF2S1ArrowR-HSA-381111 (Reactome)
p-S52-EIF2S1ArrowR-HSA-381128 (Reactome)
p-S724-IRE1 dimer:ADPArrowR-HSA-381116 (Reactome)
p-S724-IRE1 dimer:ADPmim-catalysisR-HSA-425923 (Reactome)
p-S724-IRE1 dimerArrowR-HSA-381091 (Reactome)
p-S724-IRE1 dimerR-HSA-381116 (Reactome)
unfolded proteinR-HSA-381086 (Reactome)
unfolded proteinR-HSA-381158 (Reactome)
unfolded proteinR-HSA-381217 (Reactome)
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