Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a membrane protein that in humans is encoded by the DERL1gene.[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]
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:
↑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. PMID26173415.
↑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. PMID29530993.
↑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. PMID19043451.
↑ 16.016.1Travers 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. PMID10847680.
↑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. PMID19509052.
↑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. PMID11740563.
↑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. PMID20375427.
↑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. PMID19632687.
↑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. PMID19515379.
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. PMID8619474.
Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E, Koning F, Kloetzel PM, Seeger M (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. PMID16289116.
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. PMID16954204.
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. PMID17453418.