Alternative titles; symbols
HGNC Approved Gene Symbol: DERL1
Cytogenetic location: 8q24.13 Genomic coordinates (GRCh38) : 8:123,013,170-123,042,302 (from NCBI)
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.
Gross (2014) mapped the DERL1 gene to chromosome 8q24.13 based on an alignment of the DERL1 sequence (GenBank BC002457) with the genomic sequence (GRCh37).
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; 616175), 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.
Gross, M. B. Personal Communication. Baltimore, Md. 6/24/2014.
Lilley, B. N., Ploegh, H. L. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429: 834-840, 2004. [PubMed: 15215855] [Full Text: https://doi.org/10.1038/nature02592]
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. [PubMed: 18519638] [Full Text: https://doi.org/10.1101/gad.1640108]
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. [PubMed: 15215856] [Full Text: https://doi.org/10.1038/nature02656]
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. [PubMed: 16901789] [Full Text: https://doi.org/10.1016/j.cell.2006.06.041]