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.
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Thuerauf DJ, Morrison L, Glembotski CC.; ''Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Scheuner D, Kaufman RJ.; ''The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Stirling J, O'hare P.; ''CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP.; ''Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Suragani RN, Kamindla R, Ehtesham NZ, Ramaiah KV.; ''Interaction of recombinant human eIF2 subunits with eIF2B and eIF2alpha kinases.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Imagawa Y, Hosoda A, Sasaka S, Tsuru A, Kohno K.; ''RNase domains determine the functional difference between IRE1alpha and IRE1beta.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ross JA, Bressler KR, Thakor N.; ''Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Shen J, Snapp EL, Lippincott-Schwartz J, Prywes R.; ''Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response.''; PubMedEurope PMCScholia
Herbert TP.; ''PERK in the life and death of the pancreatic beta-cell.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Schröder M, Kaufman RJ.; ''The mammalian unfolded protein response.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Llarena M, Bailey D, Curtis H, O'Hare P.; ''Different mechanisms of recognition and ER retention by transmembrane transcription factors CREB-H and ATF6.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Lee AH, Iwakoshi NN, Glimcher LH.; ''XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Meyerovich K, Ortis F, Allagnat F, Cardozo AK.; ''Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Audas TE, Li Y, Liang G, Lu R.; ''A novel protein, Luman/CREB3 recruitment factor, inhibits Luman activation of the unfolded protein response.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P.; ''On the mechanism of sensing unfolded protein in the endoplasmic reticulum.''; PubMedEurope PMCScholia
Uemura A, Oku M, Mori K, Yoshida H.; ''Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during the mammalian unfolded protein response.''; PubMedEurope PMCScholia
Kakiuchi C, Ishiwata M, Hayashi A, Kato T.; ''XBP1 induces WFS1 through an endoplasmic reticulum stress response element-like motif in SH-SY5Y cells.''; PubMedEurope PMCScholia
Denard B, Lee C, Ye J.; ''Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1.''; PubMedEurope PMCScholia
Fox RM, Andrew DJ.; ''Transcriptional regulation of secretory capacity by bZip transcription factors.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Liu CY, Schröder M, Kaufman RJ.; ''Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Eizirik DL, Cardozo AK, Cnop M.; ''The role for endoplasmic reticulum stress in diabetes mellitus.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Marchand A, Tomkiewicz C, Magne L, Barouki R, Garlatti M.; ''Endoplasmic reticulum stress induction of insulin-like growth factor-binding protein-1 involves ATF4.''; PubMedEurope PMCScholia
Iwawaki T, Akai R.; ''Analysis of the XBP1 splicing mechanism using endoplasmic reticulum stress-indicators.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.
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.
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.
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.
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 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)
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.
The C-terminal domain of PERK 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.
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.
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.
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).
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.
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.
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.
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.
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.
PERK 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.
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.
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
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.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=381119
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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.
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.
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).