Unfolded Protein Response (UPR) (Homo sapiens)

From WikiPathways

Jump to: navigation, search
21, 24, 27, 51, 54...26, 34, 60421746, 49, 627, 22, 4314, 15, 5626, 28, 3419, 255, 33, 45, 50, 578, 687, 22, 432530, 40, 47, 5931, 47, 5919, 2528, 3414, 15, 568, 12, 36, 61, 66...44, 52, 55, 7014, 25, 3810, 1625, 26, 28, 3414, 15, 25, 561033, 50, 578, 6818, 23, 443, 639, 30, 475, 33, 45, 50, 5713, 4319, 25, 6446, 49, 62cytosolnucleoplasmendoplasmic reticulum lumenGolgi lumenCREB3L2(1-379)BiP:Unfolded ProteinATF6(1-419)ATF6(380-419)XBP1(S) activateschaperone genesHSPA5 HSPA5 ATF6:BiPMBTPS1ATF4Xbp1 mRNA (spliced)CREB3(1-256) EIF2AK3 ATF6 CREBRF CREB3L4CREB3:CREBRFp-S724-IRE1 dimerDCSTAMP:CREB3ATF6 (ATF6-alpha)activates chaperonegenesCREB3L1(427-519)IRE1:BiPCREB3(257-291)ERN1XBP1-2CREB3L2(380-430)ADPp-S724-ERN1 CREB3L3(324-364)p-S724-ERN1 EIF2AK3CREB3L1CREBRFCREB3L4(1-297)ATF6(1-380)ERN1 ATPCREB3L2CREB3L3(1-323)IRE1 dimerATF6CREB3(292-395)unfolded protein HSPA5 CREB3(1-291)CREB3L1ADPCREB3L4(1-338)EIF2AK3 CREB3L4DCSTAMP CREB3(1-256)CREB3 ATF4 mRNAHSPA5 CREB3EIF2S1CREB3L4(1-297)CREB3L1(1-375)ATF4 activates genesCREB3L2(431-520)ATF6(1-380)p-S52-EIF2S1CREB3L3p-S724-IRE1dimer:ADPCREB3L1(1-375)ATPCREB3L1(376-426)CREB3L3CREB3L2CREB3L4(298-338)CREB3L1(1-426)ATF6ERN1 CREB3L4(339-395)CREB3L2(1-430)CREB3L3(365-461)CREB3L3(1-323)ADP CREB3L3(1-364)CREB3L2(1-379)Xbp1 mRNA(unspliced)unfolded proteinMBTPS2PERK dimerATF6(420-670)PERK:BiPCREB3(1-256)31, 47, 5931, 47, 5913, 29, 32, 37, 41...5656566, 18, 35, 39, 675631, 47, 5925222231, 47, 59225625421, 3, 4, 11, 20...56252214, 7125


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, ATF6B, CREB3 factors and IRE1 leads to increased transcription of genes encoding chaperones, while mobilization of PERK (pancreatic eIF2alpha kinase, EIF2AK3) leads to phosphorylation of the translation initiation factor eIF2alpha and global down-regulation of protein synthesis.
ATF6, ATF6B, and CREB3 factors (CREB3 (LUMAN), CREB3L1 (OASIS), CREB3L2 (BBF2H7, Tisp40), CREB3L3 (CREB-H), and CREB3L4 (CREB4)) are membrane-bound transcription activators that respond to ER stress by transiting from the ER membrane to the Golgi membrane where their transmembrane domains are cleaved, releasing their cytosolic domains to transit to the nucleus and activate transcription of target genes. IRE1, also a resident of the ER membrane, dimerizes and autophosphorylates in response to ER stress. The activated IRE1 then catalyzes unconventional splicing of XBP1 mRNA to yield an XBP1 isoform that is targeted to the nucleus and activates chaperone genes. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 381119
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

Quality Tags

Ontology Terms



View all...
  1. Marchand A, Tomkiewicz C, Magne L, Barouki R, Garlatti M.; ''Endoplasmic reticulum stress induction of insulin-like growth factor-binding protein-1 involves ATF4.''; PubMed Europe PMC
  2. Murakami T, Kondo S, Ogata M, Kanemoto S, Saito A, Wanaka A, Imaizumi K.; ''Cleavage of the membrane-bound transcription factor OASIS in response to endoplasmic reticulum stress.''; PubMed Europe PMC
  3. Yamaguchi Y, Larkin D, Lara-Lemus R, Ramos-Castañeda J, Liu M, Arvan P.; ''Endoplasmic reticulum (ER) chaperone regulation and survival of cells compensating for deficiency in the ER stress response kinase, PERK.''; PubMed Europe PMC
  4. Gargalovic PS, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Baruch-Oren T, Berliner JA, Kirchgessner TG, Lusis AJ.; ''The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.''; PubMed Europe PMC
  5. Mellor P, Deibert L, Calvert B, Bonham K, Carlsen SA, Anderson DH.; ''CREB3L1 is a metastasis suppressor that represses expression of genes regulating metastasis, invasion, and angiogenesis.''; PubMed Europe PMC
  6. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht BD.; ''XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks.''; PubMed Europe PMC
  7. Shen J, Prywes R.; ''Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6.''; PubMed Europe PMC
  8. Herbert TP.; ''PERK in the life and death of the pancreatic beta-cell.''; PubMed Europe PMC
  9. Oikawa D, Kimata Y, Kohno K, Iwawaki T.; ''Activation of mammalian IRE1alpha upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins.''; PubMed Europe PMC
  10. Kondo S, Hino SI, Saito A, Kanemoto S, Kawasaki N, Asada R, Izumi S, Iwamoto H, Oki M, Miyagi H, Kaneko M, Nomura Y, Urano F, Imaizumi K.; ''Activation of OASIS family, ER stress transducers, is dependent on its stabilization.''; PubMed Europe PMC
  11. Gjymishka A, Su N, Kilberg MS.; ''Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway.''; PubMed Europe PMC
  12. Suragani RN, Kamindla R, Ehtesham NZ, Ramaiah KV.; ''Interaction of recombinant human eIF2 subunits with eIF2B and eIF2alpha kinases.''; PubMed Europe PMC
  13. Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R.; ''Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response.''; PubMed Europe PMC
  14. Eleveld-Trancikova D, Sanecka A, van Hout-Kuijer MA, Looman MW, Hendriks IA, Jansen BJ, Adema GJ.; ''DC-STAMP interacts with ER-resident transcription factor LUMAN which becomes activated during DC maturation.''; PubMed Europe PMC
  15. Liang G, Audas TE, Li Y, Cockram GP, Dean JD, Martyn AC, Kokame K, Lu R.; ''Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element.''; PubMed Europe PMC
  16. Panagopoulos I, Möller E, Dahlén A, Isaksson M, Mandahl N, Vlamis-Gardikas A, Mertens F.; ''Characterization of the native CREB3L2 transcription factor and the FUS/CREB3L2 chimera.''; PubMed Europe PMC
  17. Iwamoto H, Matsuhisa K, Saito A, Kanemoto S, Asada R, Hino K, Takai T, Cui M, Cui X, Kaneko M, Arihiro K, Sugiyama K, Kurisu K, Matsubara A, Imaizumi K.; ''Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7.''; PubMed Europe PMC
  18. Yoshida H, Oku M, Suzuki M, Mori K.; ''pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response.''; PubMed Europe PMC
  19. Ben Aicha S, Lessard J, Pelletier M, Fournier A, Calvo E, Labrie C.; ''Transcriptional profiling of genes that are regulated by the endoplasmic reticulum-bound transcription factor AIbZIP/CREB3L4 in prostate cells.''; PubMed Europe PMC
  20. Ma Y, Hendershot LM.; ''Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways.''; PubMed Europe PMC
  21. Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P.; ''On the mechanism of sensing unfolded protein in the endoplasmic reticulum.''; PubMed Europe PMC
  22. Ye J, Rawson RB, Komuro R, Chen X, Davé UP, Prywes R, Brown MS, Goldstein JL.; ''ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.''; PubMed Europe PMC
  23. Clauss IM, Chu M, Zhao JL, Glimcher LH.; ''The basic domain/leucine zipper protein hXBP-1 preferentially binds to and transactivates CRE-like sequences containing an ACGT core.''; PubMed Europe PMC
  24. Meyerovich K, Ortis F, Allagnat F, Cardozo AK.; ''Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation.''; PubMed Europe PMC
  25. Stirling J, O'hare P.; ''CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P.''; PubMed Europe PMC
  26. Llarena M, Bailey D, Curtis H, O'Hare P.; ''Different mechanisms of recognition and ER retention by transmembrane transcription factors CREB-H and ATF6.''; PubMed Europe PMC
  27. Schröder M.; ''Endoplasmic reticulum stress responses.''; PubMed Europe PMC
  28. Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, Back SH, Kaufman RJ.; ''Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response.''; PubMed Europe PMC
  29. Thuerauf DJ, Morrison L, Glembotski CC.; ''Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction.''; PubMed Europe PMC
  30. Liu CY, Wong HN, Schauerte JA, Kaufman RJ.; ''The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain.''; PubMed Europe PMC
  31. Tirasophon W, Welihinda AA, Kaufman RJ.; ''A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells.''; PubMed Europe PMC
  32. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K.; ''ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response.''; PubMed Europe PMC
  33. Ward AK, Mellor P, Smith SE, Kendall S, Just NA, Vizeacoumar FS, Sarker S, Phillips Z, Alvi R, Saxena A, Vizeacoumar FJ, Carlsen SA, Anderson DH.; ''Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers.''; PubMed Europe PMC
  34. Bailey D, Barreca C, O'Hare P.; ''Trafficking of the bZIP transmembrane transcription factor CREB-H into alternate pathways of ERAD and stress-regulated intramembrane proteolysis.''; PubMed Europe PMC
  35. Yamamoto K, Suzuki N, Wada T, Okada T, Yoshida H, Kaufman RJ, Mori K.; ''Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds.''; PubMed Europe PMC
  36. Shi Y, An J, Liang J, Hayes SE, Sandusky GE, Stramm LE, Yang NN.; ''Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells.''; PubMed Europe PMC
  37. Li M, Baumeister P, Roy B, Phan T, Foti D, Luo S, Lee AS.; ''ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1.''; PubMed Europe PMC
  38. Lu R, Yang P, O'Hare P, Misra V.; ''Luman, a new member of the CREB/ATF family, binds to herpes simplex virus VP16-associated host cellular factor.''; PubMed Europe PMC
  39. Lee AH, Iwakoshi NN, Glimcher LH.; ''XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.''; PubMed Europe PMC
  40. Liu CY, Schröder M, Kaufman RJ.; ''Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum.''; PubMed Europe PMC
  41. Okada T, Yoshida H, Akazawa R, Negishi M, Mori K.; ''Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response.''; PubMed Europe PMC
  42. Audas TE, Li Y, Liang G, Lu R.; ''A novel protein, Luman/CREB3 recruitment factor, inhibits Luman activation of the unfolded protein response.''; PubMed Europe PMC
  43. Haze K, Yoshida H, Yanagi H, Yura T, Mori K.; ''Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.''; PubMed Europe PMC
  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
  45. Denard B, Lee C, Ye J.; ''Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1.''; PubMed Europe PMC
  46. Shen J, Chen X, Hendershot L, Prywes R.; ''ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.''; PubMed Europe PMC
  47. Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ.; ''The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response.''; PubMed Europe PMC
  48. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP.; ''Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells.''; PubMed Europe PMC
  49. Chen X, Shen J, Prywes R.; ''The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi.''; PubMed Europe PMC
  50. Rose M, Schubert C, Dierichs L, Gaisa NT, Heer M, Heidenreich A, Knüchel R, Dahl E.; ''OASIS/CREB3L1 is epigenetically silenced in human bladder cancer facilitating tumor cell spreading and migration in vitro.''; PubMed Europe PMC
  51. Scheuner D, Kaufman RJ.; ''The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes.''; PubMed Europe PMC
  52. Uemura A, Oku M, Mori K, Yoshida H.; ''Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during the mammalian unfolded protein response.''; PubMed Europe PMC
  53. Fox RM, Andrew DJ.; ''Transcriptional regulation of secretory capacity by bZip transcription factors.''; PubMed Europe PMC
  54. Schröder M, Kaufman RJ.; ''The mammalian unfolded protein response.''; PubMed Europe PMC
  55. Imagawa Y, Hosoda A, Sasaka S, Tsuru A, Kohno K.; ''RNase domains determine the functional difference between IRE1alpha and IRE1beta.''; PubMed Europe PMC
  56. Raggo C, Rapin N, Stirling J, Gobeil P, Smith-Windsor E, O'Hare P, Misra V.; ''Luman, the cellular counterpart of herpes simplex virus VP16, is processed by regulated intramembrane proteolysis.''; PubMed Europe PMC
  57. Denard B, Seemann J, Chen Q, Gay A, Huang H, Chen Y, Ye J.; ''The membrane-bound transcription factor CREB3L1 is activated in response to virus infection to inhibit proliferation of virus-infected cells.''; PubMed Europe PMC
  58. Eizirik DL, Cardozo AK, Cnop M.; ''The role for endoplasmic reticulum stress in diabetes mellitus.''; PubMed Europe PMC
  59. Tirasophon W, Lee K, Callaghan B, Welihinda A, Kaufman RJ.; ''The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response.''; PubMed Europe PMC
  60. Omori Y, Imai J, Watanabe M, Komatsu T, Suzuki Y, Kataoka K, Watanabe S, Tanigami A, Sugano S.; ''CREB-H: a novel mammalian transcription factor belonging to the CREB/ATF family and functioning via the box-B element with a liver-specific expression.''; PubMed Europe PMC
  61. Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A, Wouters BG.; ''Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha.''; PubMed Europe PMC
  62. Shen J, Snapp EL, Lippincott-Schwartz J, Prywes R.; ''Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response.''; PubMed Europe PMC
  63. Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC.; ''Activating transcription factor 4 is translationally regulated by hypoxic stress.''; PubMed Europe PMC
  64. Qi H, Fillion C, Labrie Y, Grenier J, Fournier A, Berger L, El-Alfy M, Labrie C.; ''AIbZIP, a novel bZIP gene located on chromosome 1q21.3 that is highly expressed in prostate tumors and of which the expression is up-regulated by androgens in LNCaP human prostate cancer cells.''; PubMed Europe PMC
  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
  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
  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
  68. Ma K, Vattem KM, Wek RC.; ''Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress.''; PubMed Europe PMC
  69. Averous J, Bruhat A, Jousse C, Carraro V, Thiel G, Fafournoux P.; ''Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation.''; PubMed Europe PMC
  70. Iwawaki T, Akai R.; ''Analysis of the XBP1 splicing mechanism using endoplasmic reticulum stress-indicators.''; PubMed Europe PMC
  71. Jansen BJ, Eleveld-Trancikova D, Sanecka A, van Hout-Kuijer M, Hendriks IA, Looman MG, Leusen JH, Adema GJ.; ''OS9 interacts with DC-STAMP and modulates its intracellular localization in response to TLR ligation.''; PubMed Europe PMC


View all...
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


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 (ATF6-alpha)

activates chaperone

PathwayR-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 ProteinP18850 (Uniprot-TrEMBL)
ATF6(1-380)ProteinP18850 (Uniprot-TrEMBL)
ATF6(1-419)ProteinP18850 (Uniprot-TrEMBL)
ATF6(380-419)ProteinP18850 (Uniprot-TrEMBL)
ATF6(420-670)ProteinP18850 (Uniprot-TrEMBL)
ATF6: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).
CREB3 ProteinO43889 (Uniprot-TrEMBL)
CREB3(1-256) ProteinO43889 (Uniprot-TrEMBL)
CREB3(1-256)ProteinO43889 (Uniprot-TrEMBL)
CREB3(1-291)ProteinO43889 (Uniprot-TrEMBL)
CREB3(257-291)ProteinO43889 (Uniprot-TrEMBL)
CREB3(292-395)ProteinO43889 (Uniprot-TrEMBL)
CREB3:CREBRFComplexR-HSA-8874847 (Reactome)
CREB3L1(1-375)ProteinQ96BA8 (Uniprot-TrEMBL)
CREB3L1(1-426)ProteinQ96BA8 (Uniprot-TrEMBL)
CREB3L1(376-426)ProteinQ96BA8 (Uniprot-TrEMBL)
CREB3L1(427-519)ProteinQ96BA8 (Uniprot-TrEMBL)
CREB3L1ProteinQ96BA8 (Uniprot-TrEMBL)
CREB3L2(1-379)ProteinQ70SY1 (Uniprot-TrEMBL)
CREB3L2(1-430)ProteinQ70SY1 (Uniprot-TrEMBL)
CREB3L2(380-430)ProteinQ70SY1 (Uniprot-TrEMBL)
CREB3L2(431-520)ProteinQ70SY1 (Uniprot-TrEMBL)
CREB3L2ProteinQ70SY1 (Uniprot-TrEMBL)
CREB3L3(1-323)ProteinQ68CJ9 (Uniprot-TrEMBL)
CREB3L3(1-364)ProteinQ68CJ9 (Uniprot-TrEMBL)
CREB3L3(324-364)ProteinQ68CJ9 (Uniprot-TrEMBL)
CREB3L3(365-461)ProteinQ68CJ9 (Uniprot-TrEMBL)
CREB3L3ProteinQ68CJ9 (Uniprot-TrEMBL)
CREB3L4(1-297)ProteinQ8TEY5 (Uniprot-TrEMBL)
CREB3L4(1-338)ProteinQ8TEY5 (Uniprot-TrEMBL)
CREB3L4(298-338)ProteinQ8TEY5 (Uniprot-TrEMBL)
CREB3L4(339-395)ProteinQ8TEY5 (Uniprot-TrEMBL)
CREB3L4ProteinQ8TEY5 (Uniprot-TrEMBL)
CREB3ProteinO43889 (Uniprot-TrEMBL)
CREBRF ProteinQ8IUR6 (Uniprot-TrEMBL)
CREBRFProteinQ8IUR6 (Uniprot-TrEMBL)
DCSTAMP ProteinQ9H295 (Uniprot-TrEMBL)
DCSTAMP:CREB3ComplexR-HSA-8874383 (Reactome)
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

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-381091 (Reactome)
ADPArrowR-HSA-381111 (Reactome)
ADPR-HSA-381116 (Reactome)
ATF4 mRNAR-HSA-381128 (Reactome)
ATF4ArrowR-HSA-381128 (Reactome)
ATF6(1-380)ArrowR-HSA-381026 (Reactome)
ATF6(1-380)ArrowR-HSA-420818 (Reactome)
ATF6(1-380)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: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)
CREB3(1-256)ArrowR-HSA-8874192 (Reactome)
CREB3(1-256)ArrowR-HSA-8874197 (Reactome)
CREB3(1-256)R-HSA-8874197 (Reactome)
CREB3(1-256)R-HSA-8874849 (Reactome)
CREB3(1-291)ArrowR-HSA-8874204 (Reactome)
CREB3(1-291)R-HSA-8874192 (Reactome)
CREB3(257-291)ArrowR-HSA-8874192 (Reactome)
CREB3(292-395)ArrowR-HSA-8874204 (Reactome)
CREB3:CREBRFArrowR-HSA-8874849 (Reactome)
CREB3ArrowR-HSA-8874200 (Reactome)
CREB3L1(1-375)ArrowR-HSA-8874193 (Reactome)
CREB3L1(1-375)ArrowR-HSA-8874194 (Reactome)
CREB3L1(1-375)R-HSA-8874193 (Reactome)
CREB3L1(1-426)ArrowR-HSA-8874212 (Reactome)
CREB3L1(1-426)R-HSA-8874194 (Reactome)
CREB3L1(376-426)ArrowR-HSA-8874194 (Reactome)
CREB3L1(427-519)ArrowR-HSA-8874212 (Reactome)
CREB3L1ArrowR-HSA-8874184 (Reactome)
CREB3L1R-HSA-8874184 (Reactome)
CREB3L1R-HSA-8874212 (Reactome)
CREB3L2(1-379)ArrowR-HSA-8874187 (Reactome)
CREB3L2(1-379)ArrowR-HSA-8874191 (Reactome)
CREB3L2(1-379)R-HSA-8874191 (Reactome)
CREB3L2(1-430)ArrowR-HSA-8874205 (Reactome)
CREB3L2(1-430)R-HSA-8874187 (Reactome)
CREB3L2(380-430)ArrowR-HSA-8874187 (Reactome)
CREB3L2(431-520)ArrowR-HSA-8874205 (Reactome)
CREB3L2ArrowR-HSA-8874198 (Reactome)
CREB3L2R-HSA-8874198 (Reactome)
CREB3L2R-HSA-8874205 (Reactome)
CREB3L3(1-323)ArrowR-HSA-8874201 (Reactome)
CREB3L3(1-323)ArrowR-HSA-8874202 (Reactome)
CREB3L3(1-323)R-HSA-8874202 (Reactome)
CREB3L3(1-364)ArrowR-HSA-8874206 (Reactome)
CREB3L3(1-364)R-HSA-8874201 (Reactome)
CREB3L3(324-364)ArrowR-HSA-8874201 (Reactome)
CREB3L3(365-461)ArrowR-HSA-8874206 (Reactome)
CREB3L3ArrowR-HSA-8874208 (Reactome)
CREB3L3R-HSA-8874206 (Reactome)
CREB3L3R-HSA-8874208 (Reactome)
CREB3L4(1-297)ArrowR-HSA-8874195 (Reactome)
CREB3L4(1-297)ArrowR-HSA-8874218 (Reactome)
CREB3L4(1-297)R-HSA-8874218 (Reactome)
CREB3L4(1-338)ArrowR-HSA-8874186 (Reactome)
CREB3L4(1-338)R-HSA-8874195 (Reactome)
CREB3L4(298-338)ArrowR-HSA-8874195 (Reactome)
CREB3L4(339-395)ArrowR-HSA-8874186 (Reactome)
CREB3L4ArrowR-HSA-8874209 (Reactome)
CREB3L4R-HSA-8874186 (Reactome)
CREB3L4R-HSA-8874209 (Reactome)
CREB3R-HSA-8874204 (Reactome)
CREBRFR-HSA-8874849 (Reactome)
DCSTAMP:CREB3R-HSA-8874200 (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)
MBTPS1mim-catalysisR-HSA-8874186 (Reactome)
MBTPS1mim-catalysisR-HSA-8874204 (Reactome)
MBTPS1mim-catalysisR-HSA-8874205 (Reactome)
MBTPS1mim-catalysisR-HSA-8874206 (Reactome)
MBTPS1mim-catalysisR-HSA-8874212 (Reactome)
MBTPS2mim-catalysisR-HSA-420818 (Reactome)
MBTPS2mim-catalysisR-HSA-8874187 (Reactome)
MBTPS2mim-catalysisR-HSA-8874192 (Reactome)
MBTPS2mim-catalysisR-HSA-8874194 (Reactome)
MBTPS2mim-catalysisR-HSA-8874195 (Reactome)
MBTPS2mim-catalysisR-HSA-8874201 (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 two 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
R-HSA-8874184 (Reactome) CREB3L1 (OASIS) is normally a short-lived protein located in the endoplasmic reticulum (ER) membrane (Kondo et al. 2012) of osteoblasts, astrocytes, intestine, salivary gland, and prostate. It is targeted for proteolytic degradation by HRD1 (inferred from mouse homologs). During ER stress CREB3L1 becomes stabilized and traffics by an uncharacterized mechanism to the Golgi membrane where it is cleaved by Golgi-resident proteases MBTPS1 (S1P) and MBTPS2 (S2P) (inferred from mouse homologs).
R-HSA-8874186 (Reactome) MBTPS1 (S1P) cleaves the lumenal domain of CREB3L4 (Stirling and O'Hare 2006, Ben-Aicha et al. 2007). Based on homology with SREBFs (SREBPs), other CREB3 proteins, and the mouse homolog Creb3l4 (Tisp40) the cleavage site is inferred to be at a RNIL motif at amino acid 338. The C-terminal domain of CREB3L4 interferes with cleavage and therefore may regulate the process (Stirling and O'Hare 2006). Dithiothreitol (DTT) causes trafficking but not cleavage of CREB3L4.
R-HSA-8874187 (Reactome) MBTPS2 (S2P) cleaves CREB3L2 near the cytoplasmic face of the transmembrane domain, releasing the cytoplasmic N-terminal domain into the cytosol (inferred from human ATF6-alpha and mouse homologs).
R-HSA-8874191 (Reactome) After cleavage by MBTPS2 the N-terminal cytoplasmic domain of CREB3L2 is released into the cytosol and traffics to the nucleus where it binds CRE-like elements in promoters of genes such as Sec23a (inferred from mouse).
R-HSA-8874192 (Reactome) CREB3 is cleaved by regulated intramembrane proteolysis (RIP) (Raggo et al. 2002, Liang et al. 2006, Eleveld-Trancikova et al. 2010). As inferred from other RIP susbsrates, MBTPS2 (S2P) is believed to cleave CREB3 after MBTPS1 (S1P) cleaves (Raggo et al. 2002). Based on homology with cleavage sites in SREBP (SREBF) homologues, the cleavage site in CREB3 is estimated to be at about amino acid 254 at the cytoplasmic face of the transmembrane domain (Raggo et al. 2002).
R-HSA-8874193 (Reactome) Cleavage by MBTPS2 releases the N-terminal domain of CREB3L1 into the cytosol and it then traffics to the nucleus (Denard et al. 2011, Rose et al. 2014, Ward et al. 2016, and inferred from mouse homologs).
R-HSA-8874194 (Reactome) After cleavage by MBTPS1 (S1P), CREB3L1 (OASIS) is cleaved by MBTPS2, yielding a 60 kDal cytosolic product (S2P) (Denard et al. 2011, Denard et al. 2012, Mellor et al. 2013, Rose et al. 2014, Ward et al. 2016, inferred from mouse homologs). By inference from SREBFs (SREBPs) the cleavage is believed to occur near the cytoplasmic face of the transmembrane domain about amino acid residue 375. The cleavage releases the N-terminal cytoplasmic domain into the cytosol.
R-HSA-8874195 (Reactome) CREB3L4 (CREB4) is cleaved near the cytoplasmic face of the transmembrane domain (Stirling and O'Hare 2006, Ben-Aicha et al. 2007). Based on homology with the mouse homolog and other CREB3 proteins, MBTPS2 (S2P) cleaves CREB3L4 and the cleavage is inferred to occur at approximately amino acid 297. The cleavage releases the N-terminal domain to the cytosol.
R-HSA-8874197 (Reactome) Based on homology with other substrates of regulated intramembrane cleavage, cleavage by regulate intramembrane proteolysis is believed to release the N-terminal cytoplasmic domain of CREB3 into the cytosol (Raggo et al. 2002, Eleveld-Trancikova et al. 2010). The fragment is then translocated into the nucleus (Raggo et al. 2002, Eleveld-Trancikova et al. 2010) where, in combination with HCF-1, it activates target genes that contain UPRE and ERSE-II elements in their promoters (Liang et al. 2006).
R-HSA-8874198 (Reactome) CREB3L2 (BBF2H7) localizes to the endoplasmic reticulum (Panagopoulos et al. 2007, Kondo et al. 2012) of cells in cartilage, lungs, spleen, gonads, and nervous system where it is normally targeted for proteolytic degradation by HRD1 (inferred from mouse homologs). During ER stress, CREB3L2 becomes stabilized and traffics by an uncharacterized mechanism to the Golgi membrane where it is activated by cleavage (inferred from mouse homologs).
R-HSA-8874200 (Reactome) CREB3 is expressed ubiquitously (Lu et al. 1997) and associates in the endoplasmic reticulum (ER) membrane (Stirling and O'Hare 2006) with DCSTAMP (Eleveld-Trancikova et al. 2010). Through an unclear mechanism, that may involve association of OS9 with unfolded proteins, CREB3 and DCSTAMP, which may remain in a complex, transit from the ER membrane to the Golgi membrane where CREB3 is activated by cleavage (Eleveld-Trancikova et al. 2010). CREB3 becomes activated during maturation of dendritic cells induced by lipopolysaccharide and cytokines (Eleveld-Trancikova et al. 2010).
R-HSA-8874201 (Reactome) After cleavage by MBTPS1, CREB3L3 in the Golgi membrane is cleaved by MBTPS2 (S2P) near the cytoplasmic face of the transmembrane domain (Bailey et al. 2007, inferred from mouse homologs in Zhang et al. 2006). By inference from cleavage of SREBFs (SREBPs), CREB3L3 is believed to be cleaved at approximately amino acid residue 323. The cleavage releases the N-terminal cytoplasmic domain into the cytosol.
R-HSA-8874202 (Reactome) The N-terminal, cleavage product of CREB3L3 traffics to the nucleus (Omori et al. 2001, Bailey et al. 2007, Llarena et al. 2010) where it can interact with ATF6 and where it is observed to bind the CRE, box B, and ATF6-bindng element, ERSE-I, and ERSE-II in promoters of target genes such as PEPCK.
R-HSA-8874204 (Reactome) In the Golgi membrane, CREB3 (LUMAN) is cleaved by regulated intramembrane proteolysis (Raggo et al. 2002, Liang et al. 2006, Stirling and O'Hare 2006, Eleveld-Trancikova et al. 2010). As inferred from other cleaved proteins, the reaction is probably catalyzedby MBTPS1 (S1P) at an RQLR motif (Stirling and O'Hare 2006).
R-HSA-8874205 (Reactome) MBTPS1 (S1P) cleaves CREB3L2 in the luminal domain. By inference from SREBFs (SREBPs) the cleavage is believed to occur at a RNLL motif at amino acid residue 430. The N-terminal product remains attached to the Golgi membrane by its transmembrane domain. The C-terminal luminal domain is eventually secreted and promotes Hedgehog signaling (Iwamoto et al. 2015).
R-HSA-8874206 (Reactome) CREB3L3 at the Golgi membrane is cleaved in the luminal domain (LLarena et al. 2010) by MBTPS1 (S1P) (Bailey et al. 2007, inferred from mouse homologs in Zhang et al. 2006). By inference from cleavage of SREBFs (SREBPs), CREB3L3 is believed to be cleaved at a RTLH motif at amino acid residue 364.
R-HSA-8874208 (Reactome) Unlike ATF6, CREB3L3 (and probably other CREB3 family members) does not interact with HSPA5 (BiP) (Llarena 2010). Instead, retention in the endoplasmic reticulum (ER) is mediated by a membrane-proximal cytoplasmic motif (Bailey et al. 2007). When the motif is deleted CREB3L3 is constitutively trafficked to the Golgi where it is cleaved (Bailey et al. 2007). In cells not experiencing ER stress, CREB3L3 is located in the ER membrane (Stirling and O'Hare 2006, Bailey et al. 2007, Llarena et al. 2010) and is rapidly turned over by the endoplasmic reticulum associated degradation (ERAD) pathway (Bailey et al. 2007). During ER stress CREB3L3 is translocated by an uncharacterized mechanism to the Golgi (Bailey et al. 2007, Llarena et al. 2010, also inferred from the mouse homolog in Zhang et al. 2006). CREB3L3 is expressed strongly in the liver and more weakly in the stomach and small intestine.
R-HSA-8874209 (Reactome) CREB3L4 (CREB4) is observed in the endoplasmic reticulum (ER) and the Golgi (Stirling and O'Hare 2006). Based on homologous transcription factors possessing transmembrane domains, CREB3L4 is inferred to traffic from the ER to the Golgi where it is activated by cleavage. Stress caused by dithiothreitol causes trafficking of CREB3L4 to the Golgi but cleavage by MBTPS1 (S1P) is not observed (Stirling and O'Hare 2006).
R-HSA-8874212 (Reactome) In the Golgi membrane, CREB3L1 (OASIS) is cleaved in its lumenal domain (Denard et al. 2011, Denard et al. 2012, Mellor et al. 2013, Rose et al. 2014, Ward et al. 2016) by MBTPS1 (S1P) (Denard et al. 2012, inferred from mouse homologs). By inference from SREBFs (SREBPs) and other CREB3 family proteins, CREB3L1 is cleaved at an RSLL motif around amino acid residue 426.
R-HSA-8874218 (Reactome) The N-terminal domain of CREB3L4 (CREB4, AIbZIP) containing the bZIP and transcription activation domains trafficks from the cytosol to the nucleus (Stirling and O'Hare 2006, inferred from mouse Creb3l4 (Tisp40)) where it activates transcription of target genes such as HSPA5 (BiP), BAG3, DNAJC12, and KDELR3 (Qi et al. 2002, Ben Aicha et al. 2007). Expression of CREB3L4 is itself induced by androgens in prostate tissue (Qi et al. 2002).
R-HSA-8874849 (Reactome) CREBRF (Luman recruitment factor, LRF) binds CREB3 in the nucleus and recruits CREB3 into nuclear foci (Audas et al. 2008). CREBRF destabilizes CREB3 and reduces the transcription activation activity of CREB3 during endoplasmic reticulum stress.
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)
Personal tools