ERN1

2018-07-16T12:28:18Z

2A00:8A60:C000:1:55D5:E3D4:E424:A6A:

{{Infobox_gene}}
The serine/threonine-protein kinase/endoribonuclease '''inositol-requiring enzyme 1 α ''' (IRE1α) is an [[enzyme]] that in humans is encoded by the ''ERN1'' [[gene]].<ref name="pmid9637683">{{cite journal |vauthors=Tirasophon W, Welihinda AA, Kaufman RJ | title = A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells | journal = Genes Dev | volume = 12 | issue = 12 | pages = 1812–24 |date=Jul 1998 | pmid = 9637683 | pmc = 316900 | doi =10.1101/gad.12.12.1812 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2081| accessdate = }}</ref>

== Function ==
The protein encoded by this [[gene]] is the ER to nucleus signalling 1 protein, a human [[Homology (biology)|homologue]] of the yeast Ire1 gene product. This protein possesses intrinsic [[kinase]] activity and an endoribonuclease activity and it is important in altering gene expression as a response to endoplasmic reticulum-based stress signals (mainly the [[unfolded protein response]]). Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.<ref name="entrez" />

== Signaling ==

IRE1α possesses two functional enzymatic domains, an [[endonuclease]] and a trans-autophosphorylation kinase domain. Upon activation, IRE1α oligomerizes and carries out an unconventional RNA [[Splicing (genetics)|splicing]] activity, removing an [[intron]] from the X-box binding protein 1 ([[XBP1]]) mRNA, and allowing it to become translated into a functional [[transcription factor]], XBP1s.<ref name="pmid11780124">{{cite journal |vauthors=Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D | title = IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA | journal = Nature | volume = 415 | issue = 6867 | pages = 92–6 |date=January 2002 | pmid = 11780124 | doi = 10.1038/415092a }}</ref> XBP1s upregulates ER [[Chaperones (biology)|chaperones]] and endoplasmic reticulum associated degradation ([[ERAD]]) genes that facilitate recovery from [[ER stress]].

== Interactions ==

ERN1 has been shown to [[Protein-protein interaction|interact]] with [[Heat shock protein 90kDa alpha (cytosolic), member A1]].<ref name="pmid12446770">{{cite journal |vauthors=Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L | title = Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha | journal = Mol. Cell. Biol. | volume = 22 | issue = 24 | pages = 8506–13 |date=December 2002 | pmid = 12446770 | pmc = 139892 | doi = 10.1128/MCB.22.24.8506-8513.2002 }}</ref>

== Inhibitors ==

Two types of inhibitors exist targeting either the catalytic core of the RNase domain or the ATP-binding pocket of the kinase domain.

=== RNase domain inhibitors ===

Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde,<ref name="pmid21303903">{{cite journal |vauthors=Volkmann K, Lucas JL, Vuga D, Wang X, Brumm D, Stiles C, Kriebel D, Der-Sarkissian A, Krishnan K, Schweitzer C, Liu Z, Malyankar UM, Chiovitti D, Canny M, Durocher D, Sicheri F, Patterson JB | title = Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease | journal = J. Biol. Chem. | volume = 286 | issue = 14 | pages = 12743–55 |date=April 2011 | pmid = 21303903 | pmc = 3069474 | doi = 10.1074/jbc.M110.199737 }}</ref> 4μ8C,<ref name="pmid22315414">{{cite journal |vauthors=Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP | title = The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 109 | issue = 15 | pages = E869–78 |date=April 2012 | pmid = 22315414 | pmc = 3326519 | doi = 10.1073/pnas.1115623109 }}</ref> MKC-3946,<ref name="pmid22538852">{{cite journal |vauthors=Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, Hu Y, Fabre C, Minami J, Ohguchi H, Kiziltepe T, Ikeda H, Kawano Y, French M, Blumenthal M, Tam V, Kertesz NL, Malyankar UM, Hokenson M, Pham T, Zeng Q, Patterson JB, Richardson PG, Munshi NC, Anderson KC | title = Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma | journal = Blood | volume = 119 | issue = 24 | pages = 5772–81 |date=June 2012 | pmid = 22538852 | pmc = 3382937 | doi = 10.1182/blood-2011-07-366633 }}</ref> STF-083010,<ref name="pmid21081713">{{cite journal |vauthors=Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC | title = Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma | journal = Blood | volume = 117 | issue = 4 | pages = 1311–4 |date=January 2011 | pmid = 21081713 | pmc = 3056474 | doi = 10.1182/blood-2010-08-303099 }}</ref> toyocamycin.<ref name="pmid22852048">{{cite journal |vauthors=Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R, Iwawaki T, Imoto M, Iida S | title = Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing | journal = Blood Cancer J | volume = 2 | issue = 7 | pages = e79 |date=July 2012 | pmid = 22852048 | pmc = 3408640 | doi = 10.1038/bcj.2012.26 }}</ref>

=== ATP-binding pocket ===

[[Sunitinib]] and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain.

Compound 3 prevents kinase activity, oligomerization and RNase activity.<ref name="pmid23086298">{{cite journal |vauthors=Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schürer SC, Oakes SA, Papa FR, Maly DJ | title = Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors | journal = Nat. Chem. Biol. | volume = 8 | issue = 12 | pages = 982–9 |date=December 2012 | pmid = 23086298 | pmc = 3508346 | doi = 10.1038/nchembio.1094 }}</ref>
{{Clear}}

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
*{{cite journal | author=Katayama T |title=Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response |journal=Nat. Cell Biol. |volume=1 |issue= 8 |pages= 479–85 |year= 2000 |pmid= 10587643 |doi= 10.1038/70265 |name-list-format=vanc| author2=Imaizumi K | author3=Sato N | display-authors=3 | last4=Miyoshi | first4=Ko | last5=Kudo | first5=Takashi | last6=Hitomi | first6=Junichi | last7=Morihara | first7=Takashi | last8=Yoneda | first8=Takunari | last9=Gomi | first9=Fumi }}
*{{cite journal | author=Urano F |title=Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1 |journal=Science |volume=287 |issue= 5453 |pages= 664–6 |year= 2000 |pmid= 10650002 |doi=10.1126/science.287.5453.664 |name-list-format=vanc| author2=Wang X | author3=Bertolotti A | display-authors=3 | last4=Zhang | first4=Y | last5=Chung | first5=P | last6=Harding | first6=HP | last7=Ron | first7=D }}
*{{cite journal | author=Dias Neto E |title=Shotgun sequencing of the human transcriptome with ORF expressed sequence tags |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 7 |pages= 3491–6 |year= 2000 |pmid= 10737800 |doi=10.1073/pnas.97.7.3491 | pmc=16267 |name-list-format=vanc| author2=Correa RG | author3=Verjovski-Almeida S | display-authors=3 | last4=Briones | first4=MR | last5=Nagai | first5=MA | last6=Da Silva Jr | first6=W | last7=Zago | first7=MA | last8=Bordin | first8=S | last9=Costa | first9=FF }}
*{{cite journal | author=Iwawaki T |title=Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress |journal=Nat. Cell Biol. |volume=3 |issue= 2 |pages= 158–64 |year= 2001 |pmid= 11175748 |doi= 10.1038/35055065 |name-list-format=vanc| author2=Hosoda A | author3=Okuda T | display-authors=3 | last4=Kamigori | first4=Yusuke | last5=Nomura-Furuwatari | first5=Chizumi | last6=Kimata | first6=Yukio | last7=Tsuru | first7=Akio | last8=Kohno | first8=Kenji }}
*{{cite journal | author=Yoneda T |title=Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress |journal=J. Biol. Chem. |volume=276 |issue= 17 |pages= 13935–40 |year= 2001 |pmid= 11278723 |doi= 10.1074/jbc.M010677200 |name-list-format=vanc| author2=Imaizumi K | author3=Oono K | display-authors=3 | last4=Yui | first4=D | last5=Gomi | first5=F | last6=Katayama | first6=T | last7=Tohyama | first7=M }}
*{{cite journal | author=Lee K |title=IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response |journal=Genes Dev. |volume=16 |issue= 4 |pages= 452–66 |year= 2002 |pmid= 11850408 |doi= 10.1101/gad.964702 | pmc=155339 |name-list-format=vanc| author2=Tirasophon W | author3=Shen X | display-authors=3 | last4=Michalak | first4=M | last5=Prywes | first5=R | last6=Okada | first6=T | last7=Yoshida | first7=H | last8=Mori | first8=K | last9=Kaufman | first9=RJ }}
*{{cite journal |vauthors=Liu CY, Wong HN, Schauerte JA, Kaufman RJ |title=The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain |journal=J. Biol. Chem. |volume=277 |issue= 21 |pages= 18346–56 |year= 2002 |pmid= 11897784 |doi= 10.1074/jbc.M112454200 }}
*{{cite journal | author=Nishitoh H |title=ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats |journal=Genes Dev. |volume=16 |issue= 11 |pages= 1345–55 |year= 2002 |pmid= 12050113 |doi= 10.1101/gad.992302 | pmc=186318 |name-list-format=vanc| author2=Matsuzawa A | author3=Tobiume K | display-authors=3 | last4=Saegusa | first4=K | last5=Takeda | first5=K | last6=Inoue | first6=K | last7=Hori | first7=S | last8=Kakizuka | first8=A | last9=Ichijo | first9=H }}
*{{cite journal | author=Marcu MG |title=Heat Shock Protein 90 Modulates the Unfolded Protein Response by Stabilizing IRE1α |journal=Mol. Cell. Biol. |volume=22 |issue= 24 |pages= 8506–13 |year= 2003 |pmid= 12446770 |doi=10.1128/MCB.22.24.8506-8513.2002 | pmc=139892 |name-list-format=vanc| author2=Doyle M | author3=Bertolotti A | display-authors=3 | last4=Ron | first4=D. | last5=Hendershot | first5=L. | last6=Neckers | first6=L. }}
*{{cite journal | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |name-list-format=vanc| author2=Feingold EA | author3=Grouse LH | display-authors=3 | last4=Derge | first4=JG | last5=Klausner | first5=RD | last6=Collins | first6=FS | last7=Wagner | first7=L | last8=Shenmen | first8=CM | last9=Schuler | first9=GD }}
*{{cite journal |vauthors=Liu CY, Xu Z, Kaufman RJ |title=Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha |journal=J. Biol. Chem. |volume=278 |issue= 20 |pages= 17680–7 |year= 2003 |pmid= 12637535 |doi= 10.1074/jbc.M300418200 }}
*{{cite journal |vauthors=Kaneko M, Niinuma Y, Nomura Y |title=Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2 |journal=Biol. Pharm. Bull. |volume=26 |issue= 7 |pages= 931–5 |year= 2004 |pmid= 12843613 |doi=10.1248/bpb.26.931 }}
*{{cite journal | author=Ota T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |name-list-format=vanc| author2=Suzuki Y | author3=Nishikawa T | display-authors=3 | last4=Otsuki | first4=Tetsuji | last5=Sugiyama | first5=Tomoyasu | last6=Irie | first6=Ryotaro | last7=Wakamatsu | first7=Ai | last8=Hayashi | first8=Koji | last9=Sato | first9=Hiroyuki }}
*{{cite journal |vauthors=Shang J, Lehrman MA |title=Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts |journal=Biochem. Biophys. Res. Commun. |volume=317 |issue= 2 |pages= 390–6 |year= 2004 |pmid= 15063770 |doi= 10.1016/j.bbrc.2004.03.058 }}
*{{cite journal | author=Oono K |title=JAB1 participates in unfolded protein responses by association and dissociation with IRE1 |journal=Neurochem. Int. |volume=45 |issue= 5 |pages= 765–72 |year= 2004 |pmid= 15234121 |doi= 10.1016/j.neuint.2004.01.003 |name-list-format=vanc| author2=Yoneda T | author3=Manabe T | display-authors=3 | last4=Yamagishi | first4=S | last5=Matsuda | first5=S | last6=Hitomi | first6=J | last7=Miyata | first7=S | last8=Mizuno | first8=T | last9=Imaizumi | first9=K }}
*{{cite journal | author=Huang ZM |title=Activation of Hepatitis B Virus S Promoter by a Cell Type-Restricted IRE1-Dependent Pathway Induced by Endoplasmic Reticulum Stress |journal=Mol. Cell. Biol. |volume=25 |issue= 17 |pages= 7522–33 |year= 2005 |pmid= 16107700 |doi= 10.1128/MCB.25.17.7522-7533.2005 | pmc=1190304 |name-list-format=vanc| author2=Tan T | author3=Yoshida H | display-authors=3 | last4=Mori | first4=K. | last5=Ma | first5=Y. | last6=Yen | first6=T. S. B. }}
*{{cite journal | author=Kimura K |title=Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes |journal=Genome Res. |volume=16 |issue= 1 |pages= 55–65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406 | pmc=1356129 |name-list-format=vanc| author2=Wakamatsu A | author3=Suzuki Y | display-authors=3 | last4=Ota | first4=T | last5=Nishikawa | first5=T | last6=Yamashita | first6=R | last7=Yamamoto | first7=J | last8=Sekine | first8=M | last9=Tsuritani | first9=K }}
*{{cite journal | author=Hetz C |title=Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha |journal=Science |volume=312 |issue= 5773 |pages= 572–6 |year= 2006 |pmid= 16645094 |doi= 10.1126/science.1123480 |name-list-format=vanc| author2=Bernasconi P | author3=Fisher J | display-authors=3 | last4=Lee | first4=AH | last5=Bassik | first5=MC | last6=Antonsson | first6=B | last7=Brandt | first7=GS | last8=Iwakoshi | first8=NN | last9=Schinzel | first9=A }}
*{{cite journal |vauthors=Oikawa D, Tokuda M, Iwawaki T |title=Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1 |journal=Biochem. Biophys. Res. Commun. |volume=360 |issue= 1 |pages= 122–7 |year= 2007 |pmid= 17585877 |doi= 10.1016/j.bbrc.2007.06.020 }}
{{refend}}

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ERN1