Full text data of DERL1
DERL1
(DER1)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Derlin-1 (Degradation in endoplasmic reticulum protein 1; DERtrin-1; Der1-like protein 1)
Derlin-1 (Degradation in endoplasmic reticulum protein 1; DERtrin-1; Der1-like protein 1)
UniProt
Q9BUN8
ID DERL1_HUMAN Reviewed; 251 AA.
AC Q9BUN8; B3KW41; E9PH19;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-2001, sequence version 1.
DT 22-JAN-2014, entry version 106.
DE RecName: Full=Derlin-1;
DE AltName: Full=Degradation in endoplasmic reticulum protein 1;
DE Short=DERtrin-1;
DE AltName: Full=Der1-like protein 1;
GN Name=DERL1; Synonyms=DER1; ORFNames=UNQ243/PRO276;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 47-131 (ISOFORM 2).
RC TISSUE=Esophagus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION,
RP MEMBRANE TOPOLOGY, TISSUE SPECIFICITY, AND INTERACTION WITH US11.
RX PubMed=15215855; DOI=10.1038/nature02592;
RA Lilley B.N., Ploegh H.L.;
RT "A membrane protein required for dislocation of misfolded proteins
RT from the ER.";
RL Nature 429:834-840(2004).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION,
RP AND INTERACTION WITH US11 AND VIMP.
RX PubMed=15215856; DOI=10.1038/nature02656;
RA Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A.;
RT "A membrane protein complex mediates retro-translocation from the ER
RT lumen into the cytosol.";
RL Nature 429:841-847(2004).
RN [7]
RP INTERACTION WITH VCP AND SYVN1.
RX PubMed=16289116; DOI=10.1016/j.jmb.2005.10.020;
RA Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S.,
RA Wiertz E., Koning F., Kloetzel P.-M., Seeger M.;
RT "The ubiquitin-domain protein HERP forms a complex with components of
RT the endoplasmic reticulum associated degradation pathway.";
RL J. Mol. Biol. 354:1021-1027(2005).
RN [8]
RP INTERACTION WITH NGLY1.
RX PubMed=16055502; DOI=10.1091/mbc.E05-04-0345;
RA Katiyar S., Joshi S., Lennarz W.J.;
RT "The retrotranslocation protein derlin-1 binds peptide:N-glycanase to
RT the endoplasmic reticulum.";
RL Mol. Biol. Cell 16:4584-4594(2005).
RN [9]
RP HOMOOLIGOMERIZATION, AND INTERACTION WITH AMFR; SYVN1; VCP AND VIMP.
RX PubMed=16186510; DOI=10.1073/pnas.0505006102;
RA Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E.,
RA Rapoport T.A.;
RT "Recruitment of the p97 ATPase and ubiquitin ligases to the site of
RT retrotranslocation at the endoplasmic reticulum membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005).
RN [10]
RP SUBCELLULAR LOCATION, OLIGOMERIZATION, AND INTERACTION WITH VIMP; VCP;
RP SEL1L AND SYVN1.
RX PubMed=16186509; DOI=10.1073/pnas.0505014102;
RA Lilley B.N., Ploegh H.L.;
RT "Multiprotein complexes that link dislocation, ubiquitination, and
RT extraction of misfolded proteins from the endoplasmic reticulum
RT membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005).
RN [11]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH DERL3
RP AND VCP.
RX PubMed=16449189; DOI=10.1083/jcb.200507057;
RA Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K.;
RT "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein
RT response and are required for ER-associated degradation.";
RL J. Cell Biol. 172:383-393(2006).
RN [12]
RP INTERACTION WITH RNF103.
RX PubMed=18675248; DOI=10.1016/j.bbrc.2008.07.126;
RA Maruyama Y., Yamada M., Takahashi K., Yamada M.;
RT "Ubiquitin ligase Kf-1 is involved in the endoplasmic reticulum-
RT associated degradation pathway.";
RL Biochem. Biophys. Res. Commun. 374:737-741(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-202, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP INTERACTION WITH YOD1.
RX PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016;
RA Ernst R., Mueller B., Ploegh H.L., Schlieker C.;
RT "The otubain YOD1 is a deubiquitinating enzyme that associates with
RT p97 to facilitate protein dislocation from the ER.";
RL Mol. Cell 36:28-38(2009).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
CC -!- FUNCTION: Functional component of endoplasmic reticulum-associated
CC degradation (ERAD) for misfolded lumenal proteins. May act by
CC forming a channel that allows the retrotranslocation of misfolded
CC proteins into the cytosol where they are ubiquitinated and
CC degraded by the proteasome. May mediate the interaction between
CC VCP and the degradation substrate. In case of infection by
CC cytomegaloviruses, it plays a central role in the export from the
CC ER and subsequent degradation of MHC class I heavy chains via its
CC interaction with US11 viral protein, which recognizes and
CC associates with MHC class I heavy chains. Also participates in the
CC degradation process of misfolded cytomegalovirus US2 protein.
CC -!- SUBUNIT: Forms homo- and heterooligomers with DERL2 and DERL3;
CC binding to DERL3 is poorer than that between DERL2 and DERL3.
CC Interacts with AMFR, VIMP/SELS, SEL1L, SYVN1 and VCP, as well as
CC with SEL1L-SYVN1 and VCP-VIMP protein complexes; this interaction
CC is weaker than that observed between DERL2 and these complexes.
CC Interacts with the cytomegalovirus US11 protein. Interacts with
CC NGLY1 and YOD1. Does not bind to EDEM1. Interacts with DNAJB9 and
CC RNF103.
CC -!- INTERACTION:
CC P51572:BCAP31; NbExp=3; IntAct=EBI-398977, EBI-77683;
CC P13569:CFTR; NbExp=2; IntAct=EBI-398977, EBI-349854;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9BUN8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BUN8-2; Sequence=VSP_041329;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- INDUCTION: Up-regulated in response to endoplasmic reticulum
CC stress via the ERN1-XBP1 pathway of the unfolded protein response
CC (UPR) (By similarity).
CC -!- SIMILARITY: Belongs to the derlin family.
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DR EMBL; AY358818; AAQ89177.1; -; mRNA.
DR EMBL; AC104316; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002457; AAH02457.1; -; mRNA.
DR EMBL; AK124086; BAG54003.1; -; mRNA.
DR RefSeq; NP_001128143.1; NM_001134671.2.
DR RefSeq; NP_077271.1; NM_024295.5.
DR UniGene; Hs.241576; -.
DR ProteinModelPortal; Q9BUN8; -.
DR IntAct; Q9BUN8; 8.
DR STRING; 9606.ENSP00000259512; -.
DR TCDB; 3.A.16.1.1; the endoplasmic reticular retrotranslocon (er-rt) family.
DR PhosphoSite; Q9BUN8; -.
DR DMDM; 50400630; -.
DR PaxDb; Q9BUN8; -.
DR PRIDE; Q9BUN8; -.
DR DNASU; 79139; -.
DR Ensembl; ENST00000259512; ENSP00000259512; ENSG00000136986.
DR Ensembl; ENST00000405944; ENSP00000384289; ENSG00000136986.
DR GeneID; 79139; -.
DR KEGG; hsa:79139; -.
DR UCSC; uc003ypl.3; human.
DR CTD; 79139; -.
DR GeneCards; GC08M124094; -.
DR HGNC; HGNC:28454; DERL1.
DR HPA; HPA016562; -.
DR MIM; 608813; gene.
DR neXtProt; NX_Q9BUN8; -.
DR PharmGKB; PA134926638; -.
DR eggNOG; COG5291; -.
DR HOGENOM; HOG000200949; -.
DR HOVERGEN; HBG105143; -.
DR InParanoid; Q9BUN8; -.
DR KO; K11519; -.
DR OMA; TRYWFAG; -.
DR OrthoDB; EOG7353XM; -.
DR PhylomeDB; Q9BUN8; -.
DR GenomeRNAi; 79139; -.
DR NextBio; 68017; -.
DR PRO; PR:Q9BUN8; -.
DR ArrayExpress; Q9BUN8; -.
DR Bgee; Q9BUN8; -.
DR CleanEx; HS_DERL1; -.
DR Genevestigator; Q9BUN8; -.
DR GO; GO:0005769; C:early endosome; IEA:Ensembl.
DR GO; GO:0030176; C:integral to endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005770; C:late endosome; IEA:Ensembl.
DR GO; GO:0042288; F:MHC class I protein binding; IDA:UniProtKB.
DR GO; GO:0004872; F:receptor activity; NAS:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:UniProtKB.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR GO; GO:0019060; P:intracellular transport of viral protein in host cell; TAS:UniProtKB.
DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IDA:UniProtKB.
DR InterPro; IPR007599; DER1.
DR PANTHER; PTHR11009; PTHR11009; 1.
DR Pfam; PF04511; DER1; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Endoplasmic reticulum;
KW Host-virus interaction; Membrane; Phosphoprotein; Polymorphism;
KW Protein transport; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport; Unfolded protein response.
FT CHAIN 1 251 Derlin-1.
FT /FTId=PRO_0000219042.
FT TOPO_DOM 1 22 Cytoplasmic (Potential).
FT TRANSMEM 23 43 Helical; Name=1; (Potential).
FT TOPO_DOM 44 59 Lumenal (Potential).
FT TRANSMEM 60 80 Helical; Name=2; (Potential).
FT TOPO_DOM 81 105 Cytoplasmic (Potential).
FT TRANSMEM 106 126 Helical; Name=3; (Potential).
FT TOPO_DOM 127 154 Lumenal (Potential).
FT TRANSMEM 155 175 Helical; Name=4; (Potential).
FT TOPO_DOM 176 251 Cytoplasmic (Potential).
FT MOD_RES 202 202 Phosphothreonine.
FT VAR_SEQ 170 189 Missing (in isoform 2).
FT /FTId=VSP_041329.
FT VARIANT 171 171 I -> V (in dbSNP:rs2272722).
FT /FTId=VAR_019516.
SQ SEQUENCE 251 AA; 28801 MW; 4A6E0DB68D9AF244 CRC64;
MSDIGDWFRS IPAITRYWFA ATVAVPLVGK LGLISPAYLF LWPEAFLYRF QIWRPITATF
YFPVGPGTGF LYLVNLYFLY QYSTRLETGA FDGRPADYLF MLLFNWICIV ITGLAMDMQL
LMIPLIMSVL YVWAQLNRDM IVSFWFGTRF KACYLPWVIL GFNYIIGGSV INELIGNLVG
HLYFFLMFRY PMDLGGRNFL STPQFLYRWL PSRRGGVSGF GVPPASMRRA ADQNGGGGRH
NWGQGFRLGD Q
//
ID DERL1_HUMAN Reviewed; 251 AA.
AC Q9BUN8; B3KW41; E9PH19;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-2001, sequence version 1.
DT 22-JAN-2014, entry version 106.
DE RecName: Full=Derlin-1;
DE AltName: Full=Degradation in endoplasmic reticulum protein 1;
DE Short=DERtrin-1;
DE AltName: Full=Der1-like protein 1;
GN Name=DERL1; Synonyms=DER1; ORFNames=UNQ243/PRO276;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 47-131 (ISOFORM 2).
RC TISSUE=Esophagus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION,
RP MEMBRANE TOPOLOGY, TISSUE SPECIFICITY, AND INTERACTION WITH US11.
RX PubMed=15215855; DOI=10.1038/nature02592;
RA Lilley B.N., Ploegh H.L.;
RT "A membrane protein required for dislocation of misfolded proteins
RT from the ER.";
RL Nature 429:834-840(2004).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION,
RP AND INTERACTION WITH US11 AND VIMP.
RX PubMed=15215856; DOI=10.1038/nature02656;
RA Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A.;
RT "A membrane protein complex mediates retro-translocation from the ER
RT lumen into the cytosol.";
RL Nature 429:841-847(2004).
RN [7]
RP INTERACTION WITH VCP AND SYVN1.
RX PubMed=16289116; DOI=10.1016/j.jmb.2005.10.020;
RA Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S.,
RA Wiertz E., Koning F., Kloetzel P.-M., Seeger M.;
RT "The ubiquitin-domain protein HERP forms a complex with components of
RT the endoplasmic reticulum associated degradation pathway.";
RL J. Mol. Biol. 354:1021-1027(2005).
RN [8]
RP INTERACTION WITH NGLY1.
RX PubMed=16055502; DOI=10.1091/mbc.E05-04-0345;
RA Katiyar S., Joshi S., Lennarz W.J.;
RT "The retrotranslocation protein derlin-1 binds peptide:N-glycanase to
RT the endoplasmic reticulum.";
RL Mol. Biol. Cell 16:4584-4594(2005).
RN [9]
RP HOMOOLIGOMERIZATION, AND INTERACTION WITH AMFR; SYVN1; VCP AND VIMP.
RX PubMed=16186510; DOI=10.1073/pnas.0505006102;
RA Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E.,
RA Rapoport T.A.;
RT "Recruitment of the p97 ATPase and ubiquitin ligases to the site of
RT retrotranslocation at the endoplasmic reticulum membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005).
RN [10]
RP SUBCELLULAR LOCATION, OLIGOMERIZATION, AND INTERACTION WITH VIMP; VCP;
RP SEL1L AND SYVN1.
RX PubMed=16186509; DOI=10.1073/pnas.0505014102;
RA Lilley B.N., Ploegh H.L.;
RT "Multiprotein complexes that link dislocation, ubiquitination, and
RT extraction of misfolded proteins from the endoplasmic reticulum
RT membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005).
RN [11]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH DERL3
RP AND VCP.
RX PubMed=16449189; DOI=10.1083/jcb.200507057;
RA Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K.;
RT "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein
RT response and are required for ER-associated degradation.";
RL J. Cell Biol. 172:383-393(2006).
RN [12]
RP INTERACTION WITH RNF103.
RX PubMed=18675248; DOI=10.1016/j.bbrc.2008.07.126;
RA Maruyama Y., Yamada M., Takahashi K., Yamada M.;
RT "Ubiquitin ligase Kf-1 is involved in the endoplasmic reticulum-
RT associated degradation pathway.";
RL Biochem. Biophys. Res. Commun. 374:737-741(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-202, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP INTERACTION WITH YOD1.
RX PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016;
RA Ernst R., Mueller B., Ploegh H.L., Schlieker C.;
RT "The otubain YOD1 is a deubiquitinating enzyme that associates with
RT p97 to facilitate protein dislocation from the ER.";
RL Mol. Cell 36:28-38(2009).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
CC -!- FUNCTION: Functional component of endoplasmic reticulum-associated
CC degradation (ERAD) for misfolded lumenal proteins. May act by
CC forming a channel that allows the retrotranslocation of misfolded
CC proteins into the cytosol where they are ubiquitinated and
CC degraded by the proteasome. May mediate the interaction between
CC VCP and the degradation substrate. In case of infection by
CC cytomegaloviruses, it plays a central role in the export from the
CC ER and subsequent degradation of MHC class I heavy chains via its
CC interaction with US11 viral protein, which recognizes and
CC associates with MHC class I heavy chains. Also participates in the
CC degradation process of misfolded cytomegalovirus US2 protein.
CC -!- SUBUNIT: Forms homo- and heterooligomers with DERL2 and DERL3;
CC binding to DERL3 is poorer than that between DERL2 and DERL3.
CC Interacts with AMFR, VIMP/SELS, SEL1L, SYVN1 and VCP, as well as
CC with SEL1L-SYVN1 and VCP-VIMP protein complexes; this interaction
CC is weaker than that observed between DERL2 and these complexes.
CC Interacts with the cytomegalovirus US11 protein. Interacts with
CC NGLY1 and YOD1. Does not bind to EDEM1. Interacts with DNAJB9 and
CC RNF103.
CC -!- INTERACTION:
CC P51572:BCAP31; NbExp=3; IntAct=EBI-398977, EBI-77683;
CC P13569:CFTR; NbExp=2; IntAct=EBI-398977, EBI-349854;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9BUN8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BUN8-2; Sequence=VSP_041329;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- INDUCTION: Up-regulated in response to endoplasmic reticulum
CC stress via the ERN1-XBP1 pathway of the unfolded protein response
CC (UPR) (By similarity).
CC -!- SIMILARITY: Belongs to the derlin family.
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DR EMBL; AY358818; AAQ89177.1; -; mRNA.
DR EMBL; AC104316; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002457; AAH02457.1; -; mRNA.
DR EMBL; AK124086; BAG54003.1; -; mRNA.
DR RefSeq; NP_001128143.1; NM_001134671.2.
DR RefSeq; NP_077271.1; NM_024295.5.
DR UniGene; Hs.241576; -.
DR ProteinModelPortal; Q9BUN8; -.
DR IntAct; Q9BUN8; 8.
DR STRING; 9606.ENSP00000259512; -.
DR TCDB; 3.A.16.1.1; the endoplasmic reticular retrotranslocon (er-rt) family.
DR PhosphoSite; Q9BUN8; -.
DR DMDM; 50400630; -.
DR PaxDb; Q9BUN8; -.
DR PRIDE; Q9BUN8; -.
DR DNASU; 79139; -.
DR Ensembl; ENST00000259512; ENSP00000259512; ENSG00000136986.
DR Ensembl; ENST00000405944; ENSP00000384289; ENSG00000136986.
DR GeneID; 79139; -.
DR KEGG; hsa:79139; -.
DR UCSC; uc003ypl.3; human.
DR CTD; 79139; -.
DR GeneCards; GC08M124094; -.
DR HGNC; HGNC:28454; DERL1.
DR HPA; HPA016562; -.
DR MIM; 608813; gene.
DR neXtProt; NX_Q9BUN8; -.
DR PharmGKB; PA134926638; -.
DR eggNOG; COG5291; -.
DR HOGENOM; HOG000200949; -.
DR HOVERGEN; HBG105143; -.
DR InParanoid; Q9BUN8; -.
DR KO; K11519; -.
DR OMA; TRYWFAG; -.
DR OrthoDB; EOG7353XM; -.
DR PhylomeDB; Q9BUN8; -.
DR GenomeRNAi; 79139; -.
DR NextBio; 68017; -.
DR PRO; PR:Q9BUN8; -.
DR ArrayExpress; Q9BUN8; -.
DR Bgee; Q9BUN8; -.
DR CleanEx; HS_DERL1; -.
DR Genevestigator; Q9BUN8; -.
DR GO; GO:0005769; C:early endosome; IEA:Ensembl.
DR GO; GO:0030176; C:integral to endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005770; C:late endosome; IEA:Ensembl.
DR GO; GO:0042288; F:MHC class I protein binding; IDA:UniProtKB.
DR GO; GO:0004872; F:receptor activity; NAS:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:UniProtKB.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR GO; GO:0019060; P:intracellular transport of viral protein in host cell; TAS:UniProtKB.
DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IDA:UniProtKB.
DR InterPro; IPR007599; DER1.
DR PANTHER; PTHR11009; PTHR11009; 1.
DR Pfam; PF04511; DER1; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Endoplasmic reticulum;
KW Host-virus interaction; Membrane; Phosphoprotein; Polymorphism;
KW Protein transport; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport; Unfolded protein response.
FT CHAIN 1 251 Derlin-1.
FT /FTId=PRO_0000219042.
FT TOPO_DOM 1 22 Cytoplasmic (Potential).
FT TRANSMEM 23 43 Helical; Name=1; (Potential).
FT TOPO_DOM 44 59 Lumenal (Potential).
FT TRANSMEM 60 80 Helical; Name=2; (Potential).
FT TOPO_DOM 81 105 Cytoplasmic (Potential).
FT TRANSMEM 106 126 Helical; Name=3; (Potential).
FT TOPO_DOM 127 154 Lumenal (Potential).
FT TRANSMEM 155 175 Helical; Name=4; (Potential).
FT TOPO_DOM 176 251 Cytoplasmic (Potential).
FT MOD_RES 202 202 Phosphothreonine.
FT VAR_SEQ 170 189 Missing (in isoform 2).
FT /FTId=VSP_041329.
FT VARIANT 171 171 I -> V (in dbSNP:rs2272722).
FT /FTId=VAR_019516.
SQ SEQUENCE 251 AA; 28801 MW; 4A6E0DB68D9AF244 CRC64;
MSDIGDWFRS IPAITRYWFA ATVAVPLVGK LGLISPAYLF LWPEAFLYRF QIWRPITATF
YFPVGPGTGF LYLVNLYFLY QYSTRLETGA FDGRPADYLF MLLFNWICIV ITGLAMDMQL
LMIPLIMSVL YVWAQLNRDM IVSFWFGTRF KACYLPWVIL GFNYIIGGSV INELIGNLVG
HLYFFLMFRY PMDLGGRNFL STPQFLYRWL PSRRGGVSGF GVPPASMRRA ADQNGGGGRH
NWGQGFRLGD Q
//
MIM
608813
*RECORD*
*FIELD* NO
608813
*FIELD* TI
*608813 DER1-LIKE DOMAIN FAMILY, MEMBER 1; DERL1
;;DEGRADATION IN ENDOPLASMIC RETICULUM 1, YEAST, HOMOLOG OF; DER1;;
read moreDERLIN 1
*FIELD* TX
CLONING
Lilley and Ploegh (2004) used an affinity purification approach to
identify human cellular proteins that interact with wildtype but not
mutant human cytomegalovirus-encoded glycoprotein US11. They identified
the DERL1 gene, which encodes a small hydrophobic protein of 251 amino
acids predicted to span the lipid bilayer 4 times, with both its amino
and carboxy termini in the cytosol. The Der1 gene encodes an
evolutionarily conserved protein, with homologs in all eukaryotes
examined by Lilley and Ploegh (2004). Yeast Der1p is known to be a
factor in the degradation of misfolded endoplasmic reticulum (ER)
proteins. Mammals have 2 additional Der1-like domain-containing proteins
homologous to DERL1, which Lilley and Ploegh (2004) called DERL2
(610304) and DERL3 (610305). DERL2 and DERL3 are about 70% identical and
probably originated from a gene duplication event in mammals.
GENE FUNCTION
Lilley and Ploegh (2004) demonstrated that Derlin-1 is a widely
expressed protein, with strong signals obtained by immunoblotting from
liver, spleen, pancreas, lung, thymus, and ovary. Despite the presence
of Derlin-1 sequences in brain cDNA libraries, immunoreactivity was not
detected in brain. Lilley and Ploegh (2004) identified Derlin-1 as an ER
membrane protein essential for US11-mediated dislocation of the major
histocompatibility complex (MHC) class I (see 142800) heavy chain from
the ER to the cytosol, and showed that Derlin-1 mediates the degradation
of 2 different type 1 membrane proteins, class I MHC heavy chain and
US2.
Ye et al. (2004) identified a p97-interacting membrane protein complex
in mammalian ER that links the recognition of a misfolded protein in the
ER lumen with its subsequent movement through the membrane by the
cytosolic p97 ATPase (VCP; 601023). The central component of the
complex, Derlin-1, was found to associate with different substrates as
they move through the membrane. Inactivation of Derlin-1 in C. elegans
caused ER stress. Ye et al. (2004) found that Derlin-1 interacts with
US11, a virally-encoded ER protein that specifically targets MHC class I
heavy chains for export from the ER, as well as with VIMP (607918), a
membrane protein that recruits the p97 ATPase and its cofactor, a
complex consisting of UFD1 (601754) and NPL4 (606590). Ye et al. (2004)
found that VIMP links Derlin-1 with the p97 ATPase complex and that
Derlin-1/VIMP is involved in US11-induced retrotranslocation.
Cystic fibrosis (219700) arises from misfolding and premature
degradation of CFTR (602421) containing a deletion of phe508 (delF508;
602421.0001). Younger et al. (2006) identified an ER membrane-associated
ubiquitin ligase complex containing the E3 RMA1 (RNF5; 602677), the E2
UBC6E (UBE2J1), and derlin-1 that cooperated with the cytosolic HSC70
(HSPA8; 600816)/CHIP (STUB1; 607207) E3 complex to triage CFTR and
delFl508. Derlin-1 retained CFTR in the ER membrane and interacted with
RMA1 and UBC6E to promote proteasomal degradation of CFTR. RMA1 could
recognize folding defects in delF508 coincident with translation,
whereas CHIP appeared to act posttranslationally. A folding defect in
delF508 detected by RMA1 involved the inability of the second
membrane-spanning domain of CFTR to productively interact with
N-terminal domains. Younger et al. (2006) concluded that the RMA1 and
CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to
monitor the folding status of CFTR and delF508.
Using mouse motor neurons and human embryonic kidney cells expressing
SOD1 (147450) proteins with amyotrophic lateral sclerosis (ALS; see
105400)-associated mutations (e.g., G93A; 147450.0008), Nishitoh et al.
(2008) showed that mutant SOD1 interacted with the C-terminal
cytoplasmic region of DERL1 and triggered ER stress through dysfunction
of ER-associated degradation. Mutant SOD1 induced formation of an Ire1
(ERN1; 604033)-Traf2 (601895)-Ask1 (MAP3K5; 602448) complex on the ER
membrane of mouse motor neurons and activated Ask1 by triggering ER
stress-induced Ire1 activation. Dissociation of mutant SOD1 from Derl1
protected motor neurons from mutant SOD1-induced cell death.
Furthermore, deletion of Ask1 partially mitigated motor neuron loss in
vitro and extended the life span of SOD1-mutant transgenic mice.
Nishitoh et al. (2008) concluded that interaction of mutant SOD1 with
DERL1 is crucial for disease progression in familial ALS.
*FIELD* RF
1. Lilley, B. N.; Ploegh, H. L.: A membrane protein required for
dislocation of misfolded proteins from the ER. Nature 429: 834-840,
2004.
2. Nishitoh, H.; Kadowaki, H.; Nagai, A.; Maruyama, T.; Yokota, T.;
Fukutomi, H.; Noguchi, T.; Matsuzawa, A.; Takeda, K.; Ichijo, H.:
ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor
neuron death by targeting Derlin-1. Genes Dev. 22: 1451-1464, 2008.
3. Ye, Y.; Shibata, Y.; Yun, C.; Ron, D.; Rapoport, T. A.: A membrane
protein complex mediates retro-translocation from the ER lumen into
the cytosol. Nature 429: 841-847, 2004.
4. Younger, J. M.; Chen, L.; Ren, H.-Y.; Rosser, M. F. N.; Turnbull,
E. L.; Fan, C.-Y.; Patterson, C.; Cyr, D. M.: Sequential quality-control
checkpoints triage misfolded cystic fibrosis transmembrane conductance
regulator. Cell 126: 571-582, 2006.
*FIELD* CN
Patricia A. Hartz - updated: 8/13/2008
Patricia A. Hartz - updated: 2/8/2007
*FIELD* CD
Ada Hamosh: 7/23/2004
*FIELD* ED
mgross: 08/13/2008
mgross: 8/13/2008
mgross: 2/8/2007
wwang: 8/9/2006
alopez: 7/23/2004
*RECORD*
*FIELD* NO
608813
*FIELD* TI
*608813 DER1-LIKE DOMAIN FAMILY, MEMBER 1; DERL1
;;DEGRADATION IN ENDOPLASMIC RETICULUM 1, YEAST, HOMOLOG OF; DER1;;
read moreDERLIN 1
*FIELD* TX
CLONING
Lilley and Ploegh (2004) used an affinity purification approach to
identify human cellular proteins that interact with wildtype but not
mutant human cytomegalovirus-encoded glycoprotein US11. They identified
the DERL1 gene, which encodes a small hydrophobic protein of 251 amino
acids predicted to span the lipid bilayer 4 times, with both its amino
and carboxy termini in the cytosol. The Der1 gene encodes an
evolutionarily conserved protein, with homologs in all eukaryotes
examined by Lilley and Ploegh (2004). Yeast Der1p is known to be a
factor in the degradation of misfolded endoplasmic reticulum (ER)
proteins. Mammals have 2 additional Der1-like domain-containing proteins
homologous to DERL1, which Lilley and Ploegh (2004) called DERL2
(610304) and DERL3 (610305). DERL2 and DERL3 are about 70% identical and
probably originated from a gene duplication event in mammals.
GENE FUNCTION
Lilley and Ploegh (2004) demonstrated that Derlin-1 is a widely
expressed protein, with strong signals obtained by immunoblotting from
liver, spleen, pancreas, lung, thymus, and ovary. Despite the presence
of Derlin-1 sequences in brain cDNA libraries, immunoreactivity was not
detected in brain. Lilley and Ploegh (2004) identified Derlin-1 as an ER
membrane protein essential for US11-mediated dislocation of the major
histocompatibility complex (MHC) class I (see 142800) heavy chain from
the ER to the cytosol, and showed that Derlin-1 mediates the degradation
of 2 different type 1 membrane proteins, class I MHC heavy chain and
US2.
Ye et al. (2004) identified a p97-interacting membrane protein complex
in mammalian ER that links the recognition of a misfolded protein in the
ER lumen with its subsequent movement through the membrane by the
cytosolic p97 ATPase (VCP; 601023). The central component of the
complex, Derlin-1, was found to associate with different substrates as
they move through the membrane. Inactivation of Derlin-1 in C. elegans
caused ER stress. Ye et al. (2004) found that Derlin-1 interacts with
US11, a virally-encoded ER protein that specifically targets MHC class I
heavy chains for export from the ER, as well as with VIMP (607918), a
membrane protein that recruits the p97 ATPase and its cofactor, a
complex consisting of UFD1 (601754) and NPL4 (606590). Ye et al. (2004)
found that VIMP links Derlin-1 with the p97 ATPase complex and that
Derlin-1/VIMP is involved in US11-induced retrotranslocation.
Cystic fibrosis (219700) arises from misfolding and premature
degradation of CFTR (602421) containing a deletion of phe508 (delF508;
602421.0001). Younger et al. (2006) identified an ER membrane-associated
ubiquitin ligase complex containing the E3 RMA1 (RNF5; 602677), the E2
UBC6E (UBE2J1), and derlin-1 that cooperated with the cytosolic HSC70
(HSPA8; 600816)/CHIP (STUB1; 607207) E3 complex to triage CFTR and
delFl508. Derlin-1 retained CFTR in the ER membrane and interacted with
RMA1 and UBC6E to promote proteasomal degradation of CFTR. RMA1 could
recognize folding defects in delF508 coincident with translation,
whereas CHIP appeared to act posttranslationally. A folding defect in
delF508 detected by RMA1 involved the inability of the second
membrane-spanning domain of CFTR to productively interact with
N-terminal domains. Younger et al. (2006) concluded that the RMA1 and
CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to
monitor the folding status of CFTR and delF508.
Using mouse motor neurons and human embryonic kidney cells expressing
SOD1 (147450) proteins with amyotrophic lateral sclerosis (ALS; see
105400)-associated mutations (e.g., G93A; 147450.0008), Nishitoh et al.
(2008) showed that mutant SOD1 interacted with the C-terminal
cytoplasmic region of DERL1 and triggered ER stress through dysfunction
of ER-associated degradation. Mutant SOD1 induced formation of an Ire1
(ERN1; 604033)-Traf2 (601895)-Ask1 (MAP3K5; 602448) complex on the ER
membrane of mouse motor neurons and activated Ask1 by triggering ER
stress-induced Ire1 activation. Dissociation of mutant SOD1 from Derl1
protected motor neurons from mutant SOD1-induced cell death.
Furthermore, deletion of Ask1 partially mitigated motor neuron loss in
vitro and extended the life span of SOD1-mutant transgenic mice.
Nishitoh et al. (2008) concluded that interaction of mutant SOD1 with
DERL1 is crucial for disease progression in familial ALS.
*FIELD* RF
1. Lilley, B. N.; Ploegh, H. L.: A membrane protein required for
dislocation of misfolded proteins from the ER. Nature 429: 834-840,
2004.
2. Nishitoh, H.; Kadowaki, H.; Nagai, A.; Maruyama, T.; Yokota, T.;
Fukutomi, H.; Noguchi, T.; Matsuzawa, A.; Takeda, K.; Ichijo, H.:
ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor
neuron death by targeting Derlin-1. Genes Dev. 22: 1451-1464, 2008.
3. Ye, Y.; Shibata, Y.; Yun, C.; Ron, D.; Rapoport, T. A.: A membrane
protein complex mediates retro-translocation from the ER lumen into
the cytosol. Nature 429: 841-847, 2004.
4. Younger, J. M.; Chen, L.; Ren, H.-Y.; Rosser, M. F. N.; Turnbull,
E. L.; Fan, C.-Y.; Patterson, C.; Cyr, D. M.: Sequential quality-control
checkpoints triage misfolded cystic fibrosis transmembrane conductance
regulator. Cell 126: 571-582, 2006.
*FIELD* CN
Patricia A. Hartz - updated: 8/13/2008
Patricia A. Hartz - updated: 2/8/2007
*FIELD* CD
Ada Hamosh: 7/23/2004
*FIELD* ED
mgross: 08/13/2008
mgross: 8/13/2008
mgross: 2/8/2007
wwang: 8/9/2006
alopez: 7/23/2004