Derlin-1

DERL1
Identifiers
Aliases	DERL1 , DER-1, DER1, derlin 1, derlin-1
External IDs	OMIM: 608813 MGI: 1915069 HomoloGene: 11483 GeneCards: DERL1
Gene location (Human) Chr. Chromosome 8 (human) [1] Band 8q24.13 Start 123,013,170 bp [1] End 123,042,302 bp [1]
Gene location (Mouse) Chr. Chromosome 15 (mouse) [2] Band 15|15 D1 Start 57,732,898 bp [2] End 57,755,844 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte islet of Langerhans stromal cell of endometrium germinal epithelium gastrocnemius muscle sperm palpebral conjunctiva tibia superficial temporal artery appendix Top expressed in seminal vesicula ciliary body fossa iris conjunctival fornix condyle motor neuron substantia nigra lacrimal gland carotid body More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding MHC class I protein binding ubiquitin protein ligase binding protease binding ubiquitin-specific protease binding ATPase binding signaling receptor activity Cellular component early endosome VCP-NPL4-UFD1 AAA ATPase complex integral component of endoplasmic reticulum membrane Derlin-1-VIMP complex integral component of membrane late endosome membrane Derlin-1 retrotranslocation complex endoplasmic reticulum endoplasmic reticulum membrane signal recognition particle receptor complex signal recognition particle Biological process Unfolded Protein Response endoplasmic reticulum unfolded protein response ERAD pathway positive regulation of protein binding protein transport protein destabilization retrograde protein transport, ER to cytosol viral process ER-associated misfolded protein catabolic process protein homooligomerization positive regulation of protein ubiquitination establishment of protein localization ubiquitin-dependent ERAD pathway response to unfolded protein protein folding transmembrane transport protein ubiquitination transport proteasome-mediated ubiquitin-dependent protein catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 79139 67819 Ensembl ENSG00000136986 ENSMUSG00000022365 UniProt Q9BUN8 Q99J56 RefSeq (mRNA) NM_001134671 NM_024295 NM_001330601 NM_001363963 NM_024207 RefSeq (protein) NP_001128143 NP_001317530 NP_077271 NP_001350892 NP_077169 Location (UCSC) Chr 8: 123.01 – 123.04 Mb Chr 15: 57.73 – 57.76 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a membrane protein that in humans is encoded by the DERL1 gene. ^{[5] [6] [7] [8]} 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. ^{[6] [8]} Derlin-1 is widely expressed in thyroid, fat, bone marrow and many other tissues. ^[9] 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] [8] [10] [11]} and are named ‘der’ for their ‘Degradation in the ER’. ^[12] Derlin-1 is a mammalian homologue of the yeast DER1 protein, a protein involved in the yeast ERAD pathway. ^{[6] [8] [12]} Moreover, derlin-1 is a member of the rhomboid-like clan of polytopic membrane proteins. ^[10]

Overexpression of derlin-1 are associated with many cancers, including colon cancer, breast cancer, bladder cancer and non-small cell lung cancer. ^{[13] [14] [15] [16] [17]}

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. ^{[6] [8]} One evidence for the existence of DERL1 was provided by Professor Tom A. Rapoport and his research group at Harvard Medical School, Boston, Massachusetts. ^[8] 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. ^[6] As the mammalian DERL1 gene was found to be a homologue of the yeast DER1 gene found in 1996, ^[12] it was named after the yeast gene. ^{[6] [8]}

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). ^[9]

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. ^{[18] [19]} The accumulation of unfolded and misfolded proteins activates an unfolded protein response (UPR) which regulate the homeostasis of the cell. ^[20] One of the strategies cells possess to ER stress as a quality control system is the ERAD pathway, ^[20] 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. ^[21]

Under ER stress, the carboxyl-terminus region of derlin-1 captures specific misfolded proteins in the ER lumen. ^[22] Derlin-1 also interacts with VIMP, an ER membrane protein that recruits the cytosolic ATPase p97 and its cofactor. ^[8] 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. ^[23] 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. ^{[6] [8] [22]} Prior to the cytosolic degradation, the retrotranslocated misfolded proteins interacts with HRDI E3 ubiquitin ligase. ^[22] This ligase ubiquitinates the misfolded proteins promoting their degradation in the cytosol by the ubiquitin-protease system (UPS). ^[22] 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. ^[24] 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. ^[25] 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. ^[26] 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. ^{[27] [28] [29]}

Interactions

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

• HRD1 ^[22]
• VIMP ^[8]
• US11 ^[8]

See also

• Derlin-2
• Derlin-3

References

1. GRCh38: Ensembl release 89: ENSG00000136986 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022365 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, et al. (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.
6. Lilley BN, Ploegh HL (June 2004). "A membrane protein required for dislocation of misfolded proteins from the ER". Nature. 429 (6994): 834–40. Bibcode:2004Natur.429..834L. doi:10.1038/nature02592. PMID   15215855. S2CID   29483256.
7. "Entrez Gene: DERL1 Der1-like domain family, member 1".
8. 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. Bibcode:2004Natur.429..841Y. doi:10.1038/nature02656. PMID   15215856. S2CID   4317750.
9. "DERL1 derlin 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-11-08.
10. 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.
11. 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.
12. 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. doi:10.1002/j.1460-2075.1996.tb00411.x. PMC   450274 . PMID   8631297.
13. Tan X, He X, Jiang Z, Wang X, Ma L, Liu L, et al. (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. S2CID   18437543.
14. 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.
15. 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.
16. 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.
17. Wu Z, Wang C, Zhang Z, Liu W, Xu H, Wang H, et al. (2016). "High Expression of Derlin-1 Is Associated with the Malignancy of Bladder Cancer in a Chinese Han Population". PLOS ONE. 11 (12): e0168351. Bibcode:2016PLoSO..1168351W. doi: 10.1371/journal.pone.0168351 . PMC   5158059 . PMID   27977784.
18. 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.
19. 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. S2CID   7652866.
20. 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. doi: 10.1016/S0092-8674(00)80835-1 . PMID   10847680. S2CID   17577016.
21. 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.
22. 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. Bibcode:2018NatSR...8.7317K. doi:10.1038/s41598-018-25724-x. PMC   5943263 . PMID   29743537.
23. 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. Bibcode:2001Natur.414..652Y. doi:10.1038/414652a. PMID   11740563. S2CID   23397533.
24. Rao B, Li S, Yao D, Wang Q, Xia Y, Jia Y, et al. (March 2021). "The cryo-EM structure of an ERAD protein channel formed by tetrameric human Derlin-1". Science Advances. 7 (10): eabe8591. Bibcode:2021SciA....7.8591R. doi:10.1126/sciadv.abe8591. PMC   7929502 . PMID   33658201.
25. Wu X, Siggel M, Ovchinnikov S, Mi W, Svetlov V, Nudler E, et al. (April 2020). "Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex". Science. 368 (6489): eaaz2449. doi:10.1126/science.aaz2449. PMC   7380553 . PMID   32327568.
26. Rao B, Wang Q, Yao D, Xia Y, Li W, Xie Y, Li S, Cao M, Shen Y, Qin A, Zhao J, Cao Y (2023-10-13). "The cryo-EM structure of the human ERAD retrotranslocation complex". Science Advances. 9 (41): eadi5656. Bibcode:2023SciA....9I5656R. doi: 10.1126/sciadv.adi5656 . ISSN   2375-2548. PMC   10575581 . PMID   37831771.
27. 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. S2CID   24379106.
28. 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.
29. 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

• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID   8619474.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, et al. (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC   139146 . PMID   9110174.
• Katiyar S, Joshi S, Lennarz WJ (October 2005). "The retrotranslocation protein Derlin-1 binds peptide:N-glycanase to the endoplasmic reticulum". Molecular Biology of the Cell. 16 (10): 4584–94. doi:10.1091/mbc.E05-04-0345. PMC   1237066 . PMID   16055502.
• Lilley BN, Ploegh HL (October 2005). "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. Bibcode:2005PNAS..10214296L. doi: 10.1073/pnas.0505014102 . PMC   1242303 . PMID   16186509.
• Ye Y, Shibata Y, Kikkert M, van Voorden S, Wiertz E, Rapoport TA (October 2005). "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. Bibcode:2005PNAS..10214132Y. doi: 10.1073/pnas.0505006102 . PMC   1242302 . PMID   16186510.
• Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E, et al. (December 2005). "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. doi:10.1016/j.jmb.2005.10.020. PMID   16289116.
• Schubert V, Da Silva JS, Dotti CG (January 2006). "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. doi:10.1083/jcb.200506136. PMC   2063654 . PMID   16449195.
• Sun F, Zhang R, Gong X, Geng X, Drain PF, Frizzell RA (December 2006). "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. doi: 10.1074/jbc.M607085200 . PMID   16954204.
• Crawshaw SG, Cross BC, Wilson CM, High S (2007). "The oligomeric state of Derlin-1 is modulated by endoplasmic reticulum stress". Molecular Membrane Biology. 24 (2): 113–20. doi:10.1080/09687860600988727. PMID   17453418. S2CID   44903284.