Disease relevance of DERL1

• On chromosome analysis of a metastasis, a stemline with karyotype 47,XY, +der1 (1 qter---1 cen::1q21---1 qter) was identified [1].
• Overexpressed Derlin-1 Inhibits ER Expansion in the Endothelial Cells Derived from Human Hepatic Cavernous Hemangioma [2].

High impact information on DERL1

• Derlin-1 serves to retain CFTR in the ER membrane and interacts with RMA1 and Ubc6e to promote CFTR's proteasomal degradation [3].
• During retrotranslocation, a substrate first interacts with Derlin-1 before p97 and other factors join the complex [4].
• We demonstrate here that Derlin-2 is an ER-resident protein that, similar to Derlin-1, participates in the degradation of proteins from the ER [5].
• An approximately 70% knockdown of endogenous Derlin-1 by RNA interference increased the steady-state levels of WT and DeltaF508 CFTR by 10-15-fold, reflecting its significant role in CFTR degradation [6].
• These findings suggest that Derlin-1 recognizes misfolded, nonubiquitylated CFTR to initiate its dislocation and degradation early in the course of CFTR biogenesis, perhaps by detecting structural instability within the first transmembrane domain [6].

Biological context of DERL1

• Simultaneous mutagenesis of the two half-sections, DER1 and DER2, of the DER sequence was required for derepression suggesting participation of multiple proteins in the DER-dependent transcriptional repression [7].
• The viral E3 ubiquitin ligase mK3 uses the Derlin/p97 endoplasmic reticulum-associated degradation pathway to mediate down-regulation of major histocompatibility complex class I proteins [8].
• Upregulation of the putative channel forming protein, derlin-1, may contribute to the increased degradation of ERAD substrates [9].
• With the noninvestigated exception of haptophytes a phylogenetically and mechanistically related system is apparently present in all chromalveolates with 4 membrane-bound plastids because amongst others, PPC-specific Derlins (Der1-like proteins), CDC48 and its cofactor Ufd1 were identified in the nuclear genomes of diatoms and apicomplexa [10].
• Knock-down of derlin-1 triggered endothelial cell apoptosis, inhibited endothelial cell proliferation, and blocked the formation of a network of tubular-like structures [11].

Anatomical context of DERL1

• The retrotranslocation protein Derlin-1 binds peptide:N-glycanase to the endoplasmic reticulum [12].
• We report that Derlin-1 and p97 formed complexes with CFTR in human airway epithelial cells [6].
• Subcellular fractionation experiments localized Zm Derlin proteins to the membrane fraction of microsomes [13].
• Our data reveal that derlin-1 is a novel growth factor-responsive endothelial antigen that promotes endothelial cell survival and growth [11].
• Derlin-1 was reportedly implicated in the retro-translocation of misfolded proteins from the ER to the cytosol for degradation [2].

Associations of DERL1 with chemical compounds

• The central component of the complex, Derlin-1, is a homologue of Der1, a yeast protein whose inactivation prevents the elimination of misfolded luminal ER proteins [14].

References