Derlin1

Derlin-1, also known as DERL1, is a conserved integral membrane protein of the endoplasmic reticulum and a member of the derlin family. In humans it is encoded by the DERL1 gene. Derlin-1 is a component of the endoplasmic reticulum–associated degradation (ERAD) pathway, a cellular quality-control system that targets misfolded proteins in the secretory pathway for removal and destruction.

Functionally, Derlin-1 participates in the retrotranslocation of misfolded substrates from the endoplasmic reticulum into the cytosol, where they are ubiquitinated and degraded by the proteasome. It is thought to contribute to a retrotranslocation channel and to operate in cooperation with other ERAD components, including the SEL1L-HRD1 complex. Derlin-1 interacts with the AAA-ATPase p97/VCP and with VIMP to assist substrate extraction from the membrane. The protein is implicated in the degradation of a broad range of substrates, including some luminal and membrane proteins.

Localization and structure: Derlin-1 is an integral membrane protein localized to the endoplasmic reticulum and is predicted to contain multiple transmembrane segments, with termini facing the cytosol. Its activity is often described in the context of ERAD complexes that assemble at various regions of the ER membrane.

Biological and clinical significance: In mammalian cells, DERL1 activity is important for efficient ERAD of several substrates. Changes in DERL1 expression have been reported in various cancers and in models of ER stress and neurodegenerative disease, though the exact contributions to disease processes are still under investigation.

Evolution: Derlin-1 is evolutionarily conserved across eukaryotes. Mammals express DERL1 along with related family members DERL2 and DERL3, while yeast possess a functional ortholog known as Der1p.