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{{Infobox_gene}}
{{Infobox_gene}}
'''Derlin-1''' also known as '''degradation in endoplasmic reticulum protein 1''' is a [[protein]] that in humans is encoded by the ''DERL1'' [[gene]].<ref name="pmid12975309">{{cite journal | vauthors = Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A | title = The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment | journal = Genome Res | volume = 13 | issue = 10 | pages = 2265–70 |date=Oct 2003 | pmid = 12975309 | pmc = 403697 | doi = 10.1101/gr.1293003 }}</ref><ref name="pmid15215855">{{cite journal | vauthors = Lilley BN, Ploegh HL | title = A membrane protein required for dislocation of misfolded proteins from the ER | journal = Nature | volume = 429 | issue = 6994 | pages = 834–40 |date=Jun 2004 | pmid = 15215855 | pmc =  | doi = 10.1038/nature02592 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DERL1 Der1-like domain family, member 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79139| accessdate = }}</ref> It is a member of the [[rhomboid protease|rhomboid]]-like clan of polytopic membrane proteins.
'''Derlin-1''' also known as '''degradation in endoplasmic reticulum protein 1''' is a [[membrane protein]] that in humans is encoded by the ''DERL1'' [[gene]].<ref name="pmid12975309">{{cite journal | vauthors = Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A | title = The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment | journal = Genome Research | volume = 13 | issue = 10 | pages = 2265–70 | date = October 2003 | pmid = 12975309 | pmc = 403697 | doi = 10.1101/gr.1293003 }}</ref><ref name="pmid15215855">{{cite journal | vauthors = Lilley BN, Ploegh HL | title = A membrane protein required for dislocation of misfolded proteins from the ER | journal = Nature | volume = 429 | issue = 6994 | pages = 834–40 | date = June 2004 | pmid = 15215855 | pmc =  | doi = 10.1038/nature02592 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DERL1 Der1-like domain family, member 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79139| access-date = }}</ref><ref name=":0">{{cite journal | vauthors = Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA | title = A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol | journal = Nature | volume = 429 | issue = 6994 | pages = 841–7 | date = June 2004 | pmid = 15215856 | doi = 10.1038/nature02656 }}</ref> Derlin-1 is located in the membrane of the [[endoplasmic reticulum]] (ER) and is involved in [[retrotranslocation]] of specific misfolded proteins and in [[ER stress]].<ref name="pmid15215855" /><ref name=":0" /> Derlin-1 is widely expressed in thyroid, fat, bone marrow and many other tissues.<ref name=":5">{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/79139#gene-expression|title=DERL1 derlin 1 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-11-08}}</ref> The protein belongs to the Derlin-family proteins (also called '''derlins''') consisting of derlin-1, [[derlin-2]] and [[derlin-3]] that are components in the [[Endoplasmic-reticulum-associated protein degradation|endoplasmic reticulum-associated protein degradation]] (ERAD) pathway. The derlins mediate degradation of misfolded lumenal proteins within ER,<ref name="pmid15215855" /><ref name=":0" /><ref name=":1">{{cite journal | vauthors = Greenblatt EJ, Olzmann JA, Kopito RR | title = Derlin-1 is a rhomboid pseudoprotease required for the dislocation of mutant α-1 antitrypsin from the endoplasmic reticulum | journal = Nature Structural & Molecular Biology | volume = 18 | issue = 10 | pages = 1147–52 | date = September 2011 | pmid = 21909096 | pmc = 3196324 | doi = 10.1038/nsmb.2111 }}</ref><ref>{{cite journal | vauthors = Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K | title = Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation | journal = The Journal of Cell Biology | volume = 172 | issue = 3 | pages = 383–93 | date = January 2006 | pmid = 16449189 | pmc = 2063648 | doi = 10.1083/jcb.200507057 }}</ref> and are named ‘der’ for their ‘Degradation in the ER’.<ref name=":2">{{cite journal | vauthors = Knop M, Finger A, Braun T, Hellmuth K, Wolf DH | title = Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast | journal = The EMBO Journal | volume = 15 | issue = 4 | pages = 753–63 | date = February 1996 | pmid = 8631297 | pmc = 450274 }}</ref> Derlin-1 is a mammalian homologue of the yeast ''[[DER1]]'' protein, a protein involved in the yeast [[Endoplasmic-reticulum-associated protein degradation|ERAD pathway]].<ref name="pmid15215855" /><ref name=":0" /><ref name=":2" /> Moreover, derlin-1 is a member of the [[rhomboid protease|rhomboid]]-like clan of polytopic membrane proteins.<ref name=":1" />


== Function ==
Overexpression of derlin-1 are associated with many cancers, including [[Colorectal cancer|colon cancer]], [[breast cancer]], [[bladder cancer]] and [[Non-small-cell lung carcinoma|non-small cell lung cancer]].<ref>{{cite journal | vauthors = Tan X, He X, Jiang Z, Wang X, Ma L, Liu L, Wang X, Fan Z, Su D | title = Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation | journal = Molecular and Cellular Biochemistry | volume = 408 | issue = 1-2 | pages = 205–13 | date = October 2015 | pmid = 26173415 | doi = 10.1007/s11010-015-2496-x }}</ref><ref>{{cite journal | vauthors = Wang J, Hua H, Ran Y, Zhang H, Liu W, Yang Z, Jiang Y | title = Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis | journal = Breast Cancer Research | volume = 10 | issue = 1 | pages = R7 | date = 2008 | pmid = 18205950 | pmc = 2374959 | doi = 10.1186/bcr1849 }}</ref><ref>{{cite journal | vauthors = Mao M, Zhang J, Jiang J | title = Overexpression of Derlin-1 is Associated with Poor Prognosis in Patients with Non-small Cell Lung Cancer | journal = Annals of Clinical and Laboratory Science | volume = 48 | issue = 1 | pages = 29–34 | date = January 2018 | pmid = 29530993 }}</ref><ref>{{cite journal | vauthors = Dong QZ, Wang Y, Tang ZP, Fu L, Li QC, Wang ED, Wang EH | title = Derlin-1 is overexpressed in non-small cell lung cancer and promotes cancer cell invasion via EGFR-ERK-mediated up-regulation of MMP-2 and MMP-9 | journal = The American Journal of Pathology | volume = 182 | issue = 3 | pages = 954–64 | date = March 2013 | pmid = 23306155 | doi = 10.1016/j.ajpath.2012.11.019 | url = https://doi.org/10.1016/j.ajpath.2012.11.019 }}</ref><ref>{{cite journal | vauthors = Wu Z, Wang C, Zhang Z, Liu W, Xu H, Wang H, Wang Y, Zhang W, Wang SL | title = High Expression of Derlin-1 Is Associated with the Malignancy of Bladder Cancer in a Chinese Han Population | journal = PLOS One | volume = 11 | issue = 12 | pages = e0168351 | date = 2016 | pmid = 27977784 | pmc = 5158059 | doi = 10.1371/journal.pone.0168351 }}</ref>


Derlin-1 is part of a complex (that includes [[SELS (gene)|VIMP]], [[SEL1]], [[SYVN1|HRD1]], and [[HERPUD1|HERP]]) that mediates endoplasmic-reticulum-associated degradation ([[Endoplasmic Reticulum Associated Protein Degradation|ERAD]]) that detects misfolded proteins in the [[endoplasmic reticulum]] and targets them for destruction.<ref name="pmid19509052">{{cite journal | vauthors = Schaheen B, Dang H, Fares H | title = Derlin-dependent accumulation of integral membrane proteins at cell surfaces | journal = J. Cell Sci. | volume = 122 | issue = Pt 13 | pages = 2228–39 |date=July 2009 | pmid = 19509052 | doi = 10.1242/jcs.048892 | url = | issn = }}</ref>
== Discovery ==
In 2004 the ''DERL1'' gene was discovered independently by two research groups when they were exploring the machinery of [[retrotranslocation]] in the ER in the cell.<ref name="pmid15215855" /><ref name=":0" /> One evidence for the existence of ''DERL1'' was provided by Professor [[Tom Rapoport|Tom A. Rapoport]] and his research group at Horward Medical School, Boston, Massachusetts.<ref name=":0" /> Another evidence of the ''DERL1'' gene was discovered by Professor [[Hidde Ploegh|Hidde L. Ploegh]] and his research group who is also at Horward Medical School, Boston, Massachusetts.<ref name="pmid15215855" /> As the mammalian ''DERL1'' gene was found to be a homologue of the yeast ''[[DER1]]'' gene found in 1996,<ref name=":2" /> it was named after the yeast gene.<ref name="pmid15215855" /><ref name=":0" />
 
== Gene location ==
The human ''DERL1'' gene is located on the long (q) arm of [[chromosome 8]] at region 2 band 4, from [[base pair]] 123,013,164 to 123,042,423 (Build GRCh37/hg19) [http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr8%3A123013164%2D123042423&hgsid=696739753_eB7l2o1dj4gS7aVj4lUGWEykzad0 (map)].<ref name=":5" />
 
== Function and mechanism ==
 
==== Rerouting factor during ER stress ====
ER stress is caused by an accumulation of unfolded or misfolded proteins in ER and is critical for cell function.<ref>{{cite journal | vauthors = Guerriero CJ, Brodsky JL | title = The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology | journal = Physiological Reviews | volume = 92 | issue = 2 | pages = 537–76 | date = April 2012 | pmid = 22535891 | pmc = 4162396 | doi = 10.1152/physrev.00027.2011 }}</ref><ref>{{cite journal | vauthors = Kim I, Xu W, Reed JC | title = Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities | journal = Nature Reviews. Drug Discovery | volume = 7 | issue = 12 | pages = 1013–30 | date = December 2008 | pmid = 19043451 | doi = 10.1038/nrd2755 }}</ref> The accumulation of unfolded and misfolded proteins activates an [[unfolded protein response]] (UPR) which regulate the homeostasis of the cell.<ref name=":3">{{cite journal | vauthors = Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P | title = Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation | journal = Cell | volume = 101 | issue = 3 | pages = 249–58 | date = April 2000 | pmid = 10847680 }}</ref> One of the strategies cells possess to [[Unfolded protein response|ER stress]] as a [[Unfolded protein response|quality control system]] is the [[Endoplasmic-reticulum-associated protein degradation|ERAD pathway]],<ref name=":3" /> by which Derlin-1 is a component of. As a part of an ER [[Translocon|membrane protein complex]] (that includes [[SELS (gene)|VIMP]], [[SEL1]], [[SYVN1|HRD1]], and [[HERPUD1|HERP]]) derlin-1 detects misfolded proteins in ER and mediate them for their degradation in the [[Endoplasmic-reticulum-associated protein degradation|ERAD pathway]].<ref name="pmid19509052">{{cite journal | vauthors = Schaheen B, Dang H, Fares H | title = Derlin-dependent accumulation of integral membrane proteins at cell surfaces | journal = Journal of Cell Science | volume = 122 | issue = Pt 13 | pages = 2228–39 | date = July 2009 | pmid = 19509052 | doi = 10.1242/jcs.048892 }}</ref>
 
Under ER stress, the [[C-terminus|carboxyl-terminus]] region of derlin-1 captures specific misfolded proteins in the ER lumen.<ref name=":4">{{cite journal | vauthors = Kadowaki H, Satrimafitrah P, Takami Y, Nishitoh H | title = Molecular mechanism of ER stress-induced pre-emptive quality control involving association of the translocon, Derlin-1, and HRD1 | language = En | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 7317 | date = May 2018 | pmid = 29743537 | pmc = 5943263 | doi = 10.1038/s41598-018-25724-x | url = https://doi.org/10.1038/s41598-018-25724-x }}</ref> Derlin-1 also interacts with [[SELS (gene)|VIMP]], an ER membrane protein that recruits the cytosolic [[P97|ATPase p97]] and its cofactor.<ref name=":0" /> The interaction of derlin-1 with p97 via VIMP is essential for export of misfolded proteins. p97 is required for the transport of the misfolded proteins through the ER membrane and back to the cytosolic side for their degradation.<ref>{{cite journal | vauthors = Ye Y, Meyer HH, Rapoport TA | title = The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol | journal = Nature | volume = 414 | issue = 6864 | pages = 652–6 | date = December 2001 | pmid = 11740563 | doi = 10.1038/414652a }}</ref> This process is referred to as [[retrotranslocation]]. Hence, one of the functions of derlin-1 is to reroute specific misfolded protein to the cytosol for their degradation.<ref name="pmid15215855" /><ref name=":0" /><ref name=":4" /> Prior to the cytosolic degradation, the retrotranslocated misfolded proteins interacts with [[SYVN1|HRDI E3 ubiquitin ligase]].<ref name=":4" /> This ligase [[ubiquitin]]ates the misfolded proteins promoting their degradation in the cytosol by the [[Proteasome|ubiquitin-protease system]] (UPS).<ref name=":4" /> Currently, the molecular mechanism by which derlin-1 reroutes the misfolded proteins from ER to their degradation are not fully understood.


== Clinical significance ==
== Clinical significance ==


Derlin 1 (DERL1) is up-regulated in metastatic canine mammary tumors as part of the unfolded protein response.<ref name=Klopfleisch4>{{cite journal |vauthors=Klopfleisch R, Klose P, Gruber AD|title=The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors.|journal=Veterinary Pathology |volume=47 |issue=3 |pages=446–54 |year=2010 |pmid=20375427 |doi=10.1177/0300985810363904}}</ref><ref name=Klopfleisch3>{{cite journal |vauthors=Klopfleisch R, Schütze M, Linzmann H, Brunnberg L, Gruber AD|title=Increased Derlin-1 expression in metastases of canine mammary adenocarcinomas.|journal=J Comp Pathol |volume=142 |issue=1 |pages=79–83 |year=2010 |pmid=19632687 |doi=10.1016/j.jcpa.2009.06.006}}</ref><ref name=Klopfleisch2>{{cite journal |vauthors=Klopfleisch R, Gruber AD|title=Derlin-1 and stanniocalcin-1 are differentially regulated in metastasizing canine mammary adenocarcinomas.|journal=J Comp Pathol. |volume=141 |issue=2 |pages=113–120 |year=2009 |pmid=19515379 |doi=10.1016/j.jcpa.2008.09.010}}</ref>
Derlin 1 (DERL1) is up-regulated in metastatic canine mammary tumors as part of the unfolded protein response.<ref name=Klopfleisch4>{{cite journal | vauthors = Klopfleisch R, Klose P, Gruber AD | title = The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors | journal = Veterinary Pathology | volume = 47 | issue = 3 | pages = 446–54 | date = May 2010 | pmid = 20375427 | doi = 10.1177/0300985810363904 }}</ref><ref name=Klopfleisch3>{{cite journal | vauthors = Klopfleisch R, Schütze M, Linzmann H, Brunnberg L, Gruber AD | title = Increased Derlin-1 expression in metastases of canine mammary adenocarcinomas | journal = Journal of Comparative Pathology | volume = 142 | issue = 1 | pages = 79–83 | date = January 2010 | pmid = 19632687 | doi = 10.1016/j.jcpa.2009.06.006 }}</ref><ref name=Klopfleisch2>{{cite journal | vauthors = Klopfleisch R, Gruber AD | title = Derlin-1 and stanniocalcin-1 are differentially regulated in metastasizing canine mammary adenocarcinomas | journal = Journal of Comparative Pathology | volume = 141 | issue = 2-3 | pages = 113–20 | year = 2009 | pmid = 19515379 | doi = 10.1016/j.jcpa.2008.09.010 }}</ref>
 
== Interactions ==
Derlin-1 has been shown to [[Protein–protein interaction|interact]] with the following proteins:
 
* HRD1<ref name=":4" />
* VIMP<ref name=":0" />
* US11<ref name=":0" />


== See also ==
== See also ==
Line 14: Line 32:
* [[Derlin-3]]
* [[Derlin-3]]


==References==
== References ==
{{reflist}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|2}}
*{{cite journal | vauthors=Andersson B, Wentland MA, Ricafrente JY |title=A "double adaptor" method for improved shotgun library construction. |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107–13 |year= 1996 |pmid= 8619474 |doi= 10.1006/abio.1996.0138 |display-authors=etal}}
* {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = April 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
*{{cite journal | vauthors=Yu W, Andersson B, Worley KC |title=Large-scale concatenation cDNA sequencing. |journal=Genome Res. |volume=7 |issue= 4 |pages= 353–8 |year= 1997 |pmid= 9110174 |doi= 10.1101/gr.7.4.353| pmc=139146  |display-authors=etal}}
* {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = April 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
*{{cite journal  | vauthors=Strausberg RL, Feingold EA, Grouse LH |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 |display-authors=etal}}
*
*{{cite journal  | vauthors=Ota T, Suzuki Y, Nishikawa 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 |display-authors=etal}}
* {{cite journal | vauthors = Katiyar S, Joshi S, Lennarz WJ | title = The retrotranslocation protein Derlin-1 binds peptide:N-glycanase to the endoplasmic reticulum | journal = Molecular Biology of the Cell | volume = 16 | issue = 10 | pages = 4584–94 | date = October 2005 | pmid = 16055502 | pmc = 1237066 | doi = 10.1091/mbc.E05-04-0345 }}
*{{cite journal  | vauthors=Ye Y, Shibata Y, Yun C |title=A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. |journal=Nature |volume=429 |issue= 6994 |pages= 841–7 |year= 2004 |pmid= 15215856 |doi= 10.1038/nature02656 |display-authors=etal}}
* {{cite journal | vauthors = Lilley BN, Ploegh HL | title = Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 40 | pages = 14296–301 | date = October 2005 | pmid = 16186509 | pmc = 1242303 | doi = 10.1073/pnas.0505014102 }}
*{{cite journal  | vauthors=Gerhard DS, Wagner L, Feingold EA |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928 |display-authors=etal}}
* {{cite journal | vauthors = Ye Y, Shibata Y, Kikkert M, van Voorden S, Wiertz E, Rapoport TA | title = Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 40 | pages = 14132–8 | date = October 2005 | pmid = 16186510 | pmc = 1242302 | doi = 10.1073/pnas.0505006102 }}
*{{cite journal | vauthors=Katiyar S, Joshi S, Lennarz WJ |title=The retrotranslocation protein Derlin-1 binds peptide:N-glycanase to the endoplasmic reticulum. |journal=Mol. Biol. Cell |volume=16 |issue= 10 |pages= 4584–94 |year= 2006 |pmid= 16055502 |doi= 10.1091/mbc.E05-04-0345 | pmc=1237066 }}
* {{cite journal | vauthors = Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E, Koning F, Kloetzel PM, Seeger M | title = The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway | journal = Journal of Molecular Biology | volume = 354 | issue = 5 | pages = 1021–7 | date = December 2005 | pmid = 16289116 | doi = 10.1016/j.jmb.2005.10.020 }}
*{{cite journal | vauthors=Lilley BN, Ploegh HL |title=Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue= 40 |pages= 14296–301 |year= 2006 |pmid= 16186509 |doi= 10.1073/pnas.0505014102 | pmc=1242303 }}
*
*{{cite journal | vauthors=Ye Y, Shibata Y, Kikkert M |title=Inaugural Article: Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue= 40 |pages= 14132–8 |year= 2006 |pmid= 16186510 |doi= 10.1073/pnas.0505006102 | pmc=1242302 |display-authors=etal}}
* {{cite journal | vauthors = Schubert V, Da Silva JS, Dotti CG | title = Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner | journal = The Journal of Cell Biology | volume = 172 | issue = 3 | pages = 453–67 | date = January 2006 | pmid = 16449195 | pmc = 2063654 | doi = 10.1083/jcb.200506136 }}
*{{cite journal | vauthors=Schulze A, Standera S, Buerger E |title=The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. |journal=J. Mol. Biol. |volume=354 |issue= 5 |pages= 1021–7 |year= 2006 |pmid= 16289116 |doi= 10.1016/j.jmb.2005.10.020 |display-authors=etal}}
* {{cite journal | vauthors = Sun F, Zhang R, Gong X, Geng X, Drain PF, Frizzell RA | title = Derlin-1 promotes the efficient degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR folding mutants | journal = The Journal of Biological Chemistry | volume = 281 | issue = 48 | pages = 36856–63 | date = December 2006 | pmid = 16954204 | doi = 10.1074/jbc.M607085200 }}
*{{cite journal  | vauthors=Oda Y, Okada T, Yoshida H |title=Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. |journal=J. Cell Biol. |volume=172 |issue= 3 |pages= 383–93 |year= 2006 |pmid= 16449189 |doi= 10.1083/jcb.200507057  | pmc=2063648 |display-authors=etal}}
* {{cite journal | vauthors = Crawshaw SG, Cross BC, Wilson CM, High S | title = The oligomeric state of Derlin-1 is modulated by endoplasmic reticulum stress | journal = Molecular Membrane Biology | volume = 24 | issue = 2 | pages = 113–20 | year = 2007 | pmid = 17453418 | doi = 10.1080/09687860600988727 }}
*{{cite journal | vauthors=Schubert V, Da Silva JS, Dotti CG |title=Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner. |journal=J. Cell Biol. |volume=172 |issue= 3 |pages= 453–67 |year= 2006 |pmid= 16449195 |doi= 10.1083/jcb.200506136 | pmc=2063654 }}
*{{cite journal | vauthors=Sun F, Zhang R, Gong X |title=Derlin-1 promotes the efficient degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR folding mutants. |journal=J. Biol. Chem. |volume=281 |issue= 48 |pages= 36856–63 |year= 2007 |pmid= 16954204 |doi= 10.1074/jbc.M607085200 |display-authors=etal}}
*{{cite journal | vauthors=Crawshaw SG, Cross BC, Wilson CM, High S |title=The oligomeric state of Derlin-1 is modulated by endoplasmic reticulum stress. |journal=Mol. Membr. Biol. |volume=24 |issue= 2 |pages= 113–20 |year= 2007 |pmid= 17453418 |doi= 10.1080/09687860600988727 }}
{{refend}}
{{refend}}
{{gene-8-stub}}

Revision as of 18:29, 27 November 2018

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SpeciesHumanMouse
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Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a membrane protein that in humans is encoded by the DERL1 gene.[1][2][3][4] Derlin-1 is located in the membrane of the endoplasmic reticulum (ER) and is involved in retrotranslocation of specific misfolded proteins and in ER stress.[2][4] Derlin-1 is widely expressed in thyroid, fat, bone marrow and many other tissues.[5] The protein belongs to the Derlin-family proteins (also called derlins) consisting of derlin-1, derlin-2 and derlin-3 that are components in the endoplasmic reticulum-associated protein degradation (ERAD) pathway. The derlins mediate degradation of misfolded lumenal proteins within ER,[2][4][6][7] and are named ‘der’ for their ‘Degradation in the ER’.[8] Derlin-1 is a mammalian homologue of the yeast DER1 protein, a protein involved in the yeast ERAD pathway.[2][4][8] Moreover, derlin-1 is a member of the rhomboid-like clan of polytopic membrane proteins.[6]

Overexpression of derlin-1 are associated with many cancers, including colon cancer, breast cancer, bladder cancer and non-small cell lung cancer.[9][10][11][12][13]

Discovery

In 2004 the DERL1 gene was discovered independently by two research groups when they were exploring the machinery of retrotranslocation in the ER in the cell.[2][4] One evidence for the existence of DERL1 was provided by Professor Tom A. Rapoport and his research group at Horward Medical School, Boston, Massachusetts.[4] Another evidence of the DERL1 gene was discovered by Professor Hidde L. Ploegh and his research group who is also at Horward Medical School, Boston, Massachusetts.[2] As the mammalian DERL1 gene was found to be a homologue of the yeast DER1 gene found in 1996,[8] it was named after the yeast gene.[2][4]

Gene location

The human DERL1 gene is located on the long (q) arm of chromosome 8 at region 2 band 4, from base pair 123,013,164 to 123,042,423 (Build GRCh37/hg19) (map).[5]

Function and mechanism

Rerouting factor during ER stress

ER stress is caused by an accumulation of unfolded or misfolded proteins in ER and is critical for cell function.[14][15] The accumulation of unfolded and misfolded proteins activates an unfolded protein response (UPR) which regulate the homeostasis of the cell.[16] One of the strategies cells possess to ER stress as a quality control system is the ERAD pathway,[16] by which Derlin-1 is a component of. As a part of an ER membrane protein complex (that includes VIMP, SEL1, HRD1, and HERP) derlin-1 detects misfolded proteins in ER and mediate them for their degradation in the ERAD pathway.[17]

Under ER stress, the carboxyl-terminus region of derlin-1 captures specific misfolded proteins in the ER lumen.[18] Derlin-1 also interacts with VIMP, an ER membrane protein that recruits the cytosolic ATPase p97 and its cofactor.[4] The interaction of derlin-1 with p97 via VIMP is essential for export of misfolded proteins. p97 is required for the transport of the misfolded proteins through the ER membrane and back to the cytosolic side for their degradation.[19] This process is referred to as retrotranslocation. Hence, one of the functions of derlin-1 is to reroute specific misfolded protein to the cytosol for their degradation.[2][4][18] Prior to the cytosolic degradation, the retrotranslocated misfolded proteins interacts with HRDI E3 ubiquitin ligase.[18] This ligase ubiquitinates the misfolded proteins promoting their degradation in the cytosol by the ubiquitin-protease system (UPS).[18] Currently, the molecular mechanism by which derlin-1 reroutes the misfolded proteins from ER to their degradation are not fully understood.

Clinical significance

Derlin 1 (DERL1) is up-regulated in metastatic canine mammary tumors as part of the unfolded protein response.[20][21][22]

Interactions

Derlin-1 has been shown to interact with the following proteins:

See also

References

  1. ↑ Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (October 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Research. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Lilley BN, Ploegh HL (June 2004). "A membrane protein required for dislocation of misfolded proteins from the ER". Nature. 429 (6994): 834–40. doi:10.1038/nature02592. PMID 15215855.
  3. ↑ "Entrez Gene: DERL1 Der1-like domain family, member 1".
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA (June 2004). "A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol". Nature. 429 (6994): 841–7. doi:10.1038/nature02656. PMID 15215856.
  5. ↑ 5.0 5.1 "DERL1 derlin 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-11-08.
  6. ↑ 6.0 6.1 Greenblatt EJ, Olzmann JA, Kopito RR (September 2011). "Derlin-1 is a rhomboid pseudoprotease required for the dislocation of mutant α-1 antitrypsin from the endoplasmic reticulum". Nature Structural & Molecular Biology. 18 (10): 1147–52. doi:10.1038/nsmb.2111. PMC 3196324. PMID 21909096.
  7. ↑ Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K (January 2006). "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation". The Journal of Cell Biology. 172 (3): 383–93. doi:10.1083/jcb.200507057. PMC 2063648. PMID 16449189.
  8. ↑ 8.0 8.1 8.2 Knop M, Finger A, Braun T, Hellmuth K, Wolf DH (February 1996). "Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast". The EMBO Journal. 15 (4): 753–63. PMC 450274. PMID 8631297.
  9. ↑ Tan X, He X, Jiang Z, Wang X, Ma L, Liu L, Wang X, Fan Z, Su D (October 2015). "Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation". Molecular and Cellular Biochemistry. 408 (1–2): 205–13. doi:10.1007/s11010-015-2496-x. PMID 26173415.
  10. ↑ Wang J, Hua H, Ran Y, Zhang H, Liu W, Yang Z, Jiang Y (2008). "Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis". Breast Cancer Research. 10 (1): R7. doi:10.1186/bcr1849. PMC 2374959. PMID 18205950.
  11. ↑ Mao M, Zhang J, Jiang J (January 2018). "Overexpression of Derlin-1 is Associated with Poor Prognosis in Patients with Non-small Cell Lung Cancer". Annals of Clinical and Laboratory Science. 48 (1): 29–34. PMID 29530993.
  12. ↑ Dong QZ, Wang Y, Tang ZP, Fu L, Li QC, Wang ED, Wang EH (March 2013). "Derlin-1 is overexpressed in non-small cell lung cancer and promotes cancer cell invasion via EGFR-ERK-mediated up-regulation of MMP-2 and MMP-9". The American Journal of Pathology. 182 (3): 954–64. doi:10.1016/j.ajpath.2012.11.019. PMID 23306155.
  13. ↑ Wu Z, Wang C, Zhang Z, Liu W, Xu H, Wang H, Wang Y, Zhang W, Wang SL (2016). "High Expression of Derlin-1 Is Associated with the Malignancy of Bladder Cancer in a Chinese Han Population". PLOS One. 11 (12): e0168351. doi:10.1371/journal.pone.0168351. PMC 5158059. PMID 27977784.
  14. ↑ Guerriero CJ, Brodsky JL (April 2012). "The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology". Physiological Reviews. 92 (2): 537–76. doi:10.1152/physrev.00027.2011. PMC 4162396. PMID 22535891.
  15. ↑ Kim I, Xu W, Reed JC (December 2008). "Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities". Nature Reviews. Drug Discovery. 7 (12): 1013–30. doi:10.1038/nrd2755. PMID 19043451.
  16. ↑ 16.0 16.1 Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P (April 2000). "Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation". Cell. 101 (3): 249–58. PMID 10847680.
  17. ↑ Schaheen B, Dang H, Fares H (July 2009). "Derlin-dependent accumulation of integral membrane proteins at cell surfaces". Journal of Cell Science. 122 (Pt 13): 2228–39. doi:10.1242/jcs.048892. PMID 19509052.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 Kadowaki H, Satrimafitrah P, Takami Y, Nishitoh H (May 2018). "Molecular mechanism of ER stress-induced pre-emptive quality control involving association of the translocon, Derlin-1, and HRD1". Scientific Reports. 8 (1): 7317. doi:10.1038/s41598-018-25724-x. PMC 5943263. PMID 29743537.
  19. ↑ Ye Y, Meyer HH, Rapoport TA (December 2001). "The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol". Nature. 414 (6864): 652–6. doi:10.1038/414652a. PMID 11740563.
  20. ↑ Klopfleisch R, Klose P, Gruber AD (May 2010). "The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors". Veterinary Pathology. 47 (3): 446–54. doi:10.1177/0300985810363904. PMID 20375427.
  21. ↑ Klopfleisch R, Schütze M, Linzmann H, Brunnberg L, Gruber AD (January 2010). "Increased Derlin-1 expression in metastases of canine mammary adenocarcinomas". Journal of Comparative Pathology. 142 (1): 79–83. doi:10.1016/j.jcpa.2009.06.006. PMID 19632687.
  22. ↑ Klopfleisch R, Gruber AD (2009). "Derlin-1 and stanniocalcin-1 are differentially regulated in metastasizing canine mammary adenocarcinomas". Journal of Comparative Pathology. 141 (2–3): 113–20. doi:10.1016/j.jcpa.2008.09.010. PMID 19515379.

Further reading

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