DERL1

Official Full Name

derlin 1

Organism

Homo sapiens

GeneID

79139

Background

The protein encoded by this gene is a member of the derlin family. Members of this family participate in the ER-associated degradation response and retrotranslocate misfolded or unfolded proteins from the ER lumen to the cytosol for proteasomal degradation. This protein recognizes substrate in the ER and works in a complex to retrotranslocate it across the ER membrane into the cytosol. This protein may select cystic fibrosis transmembrane conductance regulator protein (CFTR) for degradation as well as unfolded proteins in Alzheimer's disease. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

Synonyms

DER1; DER-1; derlin-1;

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Detailed Information

Derlin-1, a key regulator of ERAD E3 ligase, is a novel negative regulator of FABP1 and hepatic lipid metabolism. Numerous studies have shown that Derlin-1, an E3 ubiquitin ligase regulator, plays a key role in recognizing misfolded proteins by promoting the formation of reversed-site channels in the endoplasmic reticulum membrane and interacts with modified target proteins in the cytoplasm via the ubiquitin-proteasome degradation pathway.

Derlin-1 Is Localized in The ER of Progenitor Cells

Derlin-1 is a tetraspanning protein with N- and C-terminal topologies oriented towards the cytoplasm. Derlin-1 is specifically required in progenitor cells for stem cell proliferation and tissue homeostasis, and the C-terminus is important for its function.

Structure and Function of Derl1

Located on the endoplasmic reticulum membrane, Derlin-1 is an influential regulatory molecule associated with the endoplasmic reticulum-associated protein degradation pathway and is involved in the transmembrane transport of misfolded proteins. In recent years, Derlin-1 has been used as an E3 ubiquitin ligase regulator to assist protein substrates to be ubiquitin-labeled and then enter the cytoplasmic proteasome for degradation. When Derlin-1 is absent or deficient, misfolded proteins are not efficiently transported to the proteasome, resulting in cellular damage. Thus, Derlin-1 plays a crucial role in maintaining intracellular protein homeostasis and preventing disease onset and progression. Previous data showed that Derlin-1 promotes ubiquitination and degradation of epithelial Na+ channels (ENaC) and affects changes in renal function. Derlin-1-FABP1 interaction promotes FABP1 degradation in the liver via the ubiquitin proteasome system. The E3 ubiquitin ligase, Trim25, is recruited and promotes polyubiquitination of FABP1 linked to Derlin-1. Derlin-1 can affect the transcription of ACOX1, which is known for catalyzing the first rate-limiting step of the peroxisomal fatty acid β-oxidation pathway for long-chain fatty acids.

Breast Cancer of Derl1

Breast cancer is one of the most frequent malignant tumors in women. It has been found that Derlin-1 is overexpressed in a variety of human cancers in addition to playing an important role in the tumor process; however, the expression pattern and function of Derlin-1 in human breast cancer are not fully understood. Derlin-1 is overexpressed at a higher rate in breast cancer compared to normal samples, and Kaplan-Meier plotter analysis suggests that Derlin-1 is a predictor of patient prognosis. As detected by immunohistochemistry, the expression of Derlin-1 was significantly up-regulated in breast cancer tissues (18/30, 60.00%) compared with corresponding paracancerous tissues (9/30, 30.00%, p < 0.05), and the expression of Derlin-1 was correlated with pathological grades.Knockdown of Derlin-1 suppressed the protein levels of p-AKT and Cyclin D1 and Caspase3 and Bax were also upregulated. expression of MTDH and ATAD2 was suppressed in Derlin-1 knockdown cells.

Derlin is Involved in ER-related Degradation

Derlin family members are involved in the reverse translocation of endoplasmic reticulum (ER) luminal proteins to the cytoplasm for ER-associated degradation (ERAD); however, proteins that promote this reverse translocation remain to be explored. Using a CRISPR library screen, derlin-2 and surf site protein 4 (Surf4) are candidate proteins that promote the degradation of cyclooxygenase-2 (COX-2, also known as PTGS2). derlin-2 acts upstream of derlin-1, whereas Surf4 acts downstream of both derlin-2 and derlin-1 to promote COX-2 degradation.

References:

Miyano K, Okamoto S, Kajikawa M, et al. Regulation of Derlin-1-mediated degradation of NADPH oxidase partner p22phox by thiol modification. Redox Biol. 2022;56:102479. doi:10.1016/j.redox.2022.102479
You H, Wen X, Wang X, et al. Derlin-1 ameliorates nonalcoholic hepatic steatosis by promoting ubiquitylation and degradation of FABP1. Free Radic Biol Med. 2023;207:260-271. doi:10.1016/j.freeradbiomed.2023.07.026
Liu Y, Wang Z, Liu H, et al. Derlin-1 functions as a growth promoter in breast cancer. Biol Chem. 2020;401(3):377-387. doi:10.1515/hsz-2018-0442

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