Derlin-1 Explained

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. 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,^{[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. Moreover, derlin-1 is a member of the rhomboid-like clan of polytopic membrane proteins.

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. One evidence for the existence of DERL1 was provided by Professor Tom A. Rapoport and his research group at Harvard Medical School, Boston, Massachusetts. Another evidence of the DERL1 gene was discovered by Professor Hidde L. Ploegh and his research group who is also at Harvard Medical School, Boston, Massachusetts. As the mammalian DERL1 gene was found to be a homologue of the yeast DER1 gene found in 1996, it was named after the yeast gene.

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).

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, 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. 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. Prior to the cytosolic degradation, the retrotranslocated misfolded proteins interacts with HRDI E3 ubiquitin ligase. This ligase ubiquitinates the misfolded proteins promoting their degradation in the cytosol by the ubiquitin-protease system (UPS). Currently, the molecular mechanism by which derlin-1 reroutes the misfolded proteins from ER to their degradation are not fully understood.

The structure of Derlin-1

The cryo-EM analysis revealed that human Derlin-1 forms a tetrameric channel across the ER membrane.^[20] Derlin-1 channel holds a short, large transmembrane funnel in the center of tetramer with a diameter about 11-13 angstrom, which might serve as a permeation pathway for misfolded protein substrates in ERAD. Each protomer in human Derlin-1 tetramer shares a high structural similarity with yeast DER1 protein or other rhomboid members.^[21] However, this channel architecture makes human derlin-1 different from other known rhomboid structures and implies its centraal role in mammalian ERAD retrotranslocation. Further structural studies showed that Derlin-1 tetramer could form a ERAD complex with AAA ATPase p97, and the conformation of Derlin-1 channel could be changed upon the ATP hydrolysis in p97 from a trans-ER membrane channel into a U-shaped half channel with an open to the lipidic environment of ER membrane.^[22] This complex structure suggests that the retrotranslocation activity of Derlin-1 could be powered by p97.

Clinical significance

Derlin 1 (DERL1) is up-regulated in metastatic canine mammary tumors as part of the unfolded protein response.^{[23] [24] [25]}

Interactions

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

• HRD1
• VIMP
• US11

See also

• Derlin-2
• Derlin-3

Further reading

• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . 6 . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
  • Katiyar S, Joshi S, Lennarz WJ . The retrotranslocation protein Derlin-1 binds peptide:N-glycanase to the endoplasmic reticulum . Molecular Biology of the Cell . 16 . 10 . 4584–94 . October 2005 . 16055502 . 1237066 . 10.1091/mbc.E05-04-0345 .
• Lilley BN, Ploegh HL . Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane . Proceedings of the National Academy of Sciences of the United States of America . 102 . 40 . 14296–301 . October 2005 . 16186509 . 1242303 . 10.1073/pnas.0505014102 . 2005PNAS..10214296L . free .
• Ye Y, Shibata Y, Kikkert M, van Voorden S, Wiertz E, Rapoport TA . Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane . Proceedings of the National Academy of Sciences of the United States of America . 102 . 40 . 14132–8 . October 2005 . 16186510 . 1242302 . 10.1073/pnas.0505006102 . 2005PNAS..10214132Y . free .
• Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E, Koning F, Kloetzel PM, Seeger M . 6 . The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway . Journal of Molecular Biology . 354 . 5 . 1021–7 . December 2005 . 16289116 . 10.1016/j.jmb.2005.10.020 .
  • Schubert V, Da Silva JS, Dotti CG . Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner . The Journal of Cell Biology . 172 . 3 . 453–67 . January 2006 . 16449195 . 2063654 . 10.1083/jcb.200506136 .
• Sun F, Zhang R, Gong X, Geng X, Drain PF, Frizzell RA . Derlin-1 promotes the efficient degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR folding mutants . The Journal of Biological Chemistry . 281 . 48 . 36856–63 . December 2006 . 16954204 . 10.1074/jbc.M607085200 . free .
• Crawshaw SG, Cross BC, Wilson CM, High S . The oligomeric state of Derlin-1 is modulated by endoplasmic reticulum stress . Molecular Membrane Biology . 24 . 2 . 113–20 . 2007 . 17453418 . 10.1080/09687860600988727 . 44903284 .

Notes and References

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2. Lilley BN, Ploegh HL . A membrane protein required for dislocation of misfolded proteins from the ER . Nature . 429 . 6994 . 834–40 . June 2004 . 15215855 . 10.1038/nature02592 . 2004Natur.429..834L . 29483256 .
3. Web site: Entrez Gene: DERL1 Der1-like domain family, member 1.
4. Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA . A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol . Nature . 429 . 6994 . 841–7 . June 2004 . 15215856 . 10.1038/nature02656 . 2004Natur.429..841Y . 4317750 .
5. Web site: DERL1 derlin 1 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. en. 2018-11-08.
6. Greenblatt EJ, Olzmann JA, Kopito RR . 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 . September 2011 . 21909096 . 3196324 . 10.1038/nsmb.2111 .
7. Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K . 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 . January 2006 . 16449189 . 2063648 . 10.1083/jcb.200507057 .
8. Knop M, Finger A, Braun T, Hellmuth K, Wolf DH . Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast . The EMBO Journal . 15 . 4 . 753–63 . February 1996 . 8631297 . 450274 . 10.1002/j.1460-2075.1996.tb00411.x .
9. Tan X, He X, Jiang Z, Wang X, Ma L, Liu L, Wang X, Fan Z, Su D . 6 . Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation . Molecular and Cellular Biochemistry . 408 . 1–2 . 205–13 . October 2015 . 26173415 . 10.1007/s11010-015-2496-x . 18437543 .
10. Wang J, Hua H, Ran Y, Zhang H, Liu W, Yang Z, Jiang Y . Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis . Breast Cancer Research . 10 . 1 . R7 . 2008 . 18205950 . 2374959 . 10.1186/bcr1849 . free .
11. Mao M, Zhang J, Jiang J . 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 . January 2018 . 29530993 .
12. Dong QZ, Wang Y, Tang ZP, Fu L, Li QC, Wang ED, Wang EH . 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 . March 2013 . 23306155 . 10.1016/j.ajpath.2012.11.019 . free .
13. Wu Z, Wang C, Zhang Z, Liu W, Xu H, Wang H, Wang Y, Zhang W, Wang SL . 6 . High Expression of Derlin-1 Is Associated with the Malignancy of Bladder Cancer in a Chinese Han Population . PLOS ONE . 11 . 12 . e0168351 . 2016 . 27977784 . 5158059 . 10.1371/journal.pone.0168351 . 2016PLoSO..1168351W . free .
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15. Kim I, Xu W, Reed JC . Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities . Nature Reviews. Drug Discovery . 7 . 12 . 1013–30 . December 2008 . 19043451 . 10.1038/nrd2755 . 7652866 .
16. Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P . Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation . Cell . 101 . 3 . 249–58 . April 2000 . 10847680 . 10.1016/S0092-8674(00)80835-1 . 17577016 . free .
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18. Kadowaki H, Satrimafitrah P, Takami Y, Nishitoh H . Molecular mechanism of ER stress-induced pre-emptive quality control involving association of the translocon, Derlin-1, and HRD1 . En . Scientific Reports . 8 . 1 . 7317 . May 2018 . 29743537 . 5943263 . 10.1038/s41598-018-25724-x . 2018NatSR...8.7317K .
19. Ye Y, Meyer HH, Rapoport TA . The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol . Nature . 414 . 6864 . 652–6 . December 2001 . 11740563 . 10.1038/414652a . 2001Natur.414..652Y . 23397533 .
20. Rao B, Li S, Yao D, Wang Q, Xia Y, Jia Y, Shen Y, Cao Y . 6 . The cryo-EM structure of an ERAD protein channel formed by tetrameric human Derlin-1 . Science Advances . 7 . 10 . eabe8591 . March 2021 . 33658201 . 7929502 . 10.1126/sciadv.abe8591 . 2021SciA....7.8591R .
21. Wu X, Siggel M, Ovchinnikov S, Mi W, Svetlov V, Nudler E, Liao M, Hummer G, Rapoport TA . 6 . Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex . Science . 368 . 6489 . eaaz2449 . April 2020 . 32327568 . 7380553 . 10.1126/science.aaz2449 .
22. Rao . Bing . Wang . Qian . Yao . Deqiang . Xia . Ying . Li . Wenguo . Xie . Yuming . Li . Shaobai . Cao . Mi . Shen . Yafeng . Qin . An . Zhao . Jie . Cao . Yu . 2023-10-13 . The cryo-EM structure of the human ERAD retrotranslocation complex . Science Advances . en . 9 . 41 . eadi5656 . 10.1126/sciadv.adi5656 . 2375-2548. free . 37831771 . 10575581 . 2023SciA....9I5656R .
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24. Klopfleisch R, Schütze M, Linzmann H, Brunnberg L, Gruber AD . Increased Derlin-1 expression in metastases of canine mammary adenocarcinomas . Journal of Comparative Pathology . 142 . 1 . 79–83 . January 2010 . 19632687 . 10.1016/j.jcpa.2009.06.006 .
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