Derlin-dependent accumulation of integral membrane proteins at cell surfaces

Basil Schaheen, Hope Dang, Hanna F Fares

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Quality-control mechanisms of protein folding of transmembrane and secreted proteins is mediated by endoplasmic-reticulum-associated degradation (ERAD), which is used to detect and to degrade misfolded proteins in the ER. The ERAD machinery consists of chaperones, transmembrane proteins and ubiquitin-associated enzymes that detect, modify, and retro-translocate the misfolded proteins to the cytoplasm for degradation by the proteasome. In contrast to ERAD, little is known about the fates of integral membrane and secreted proteins that become misfolded at the plasma membrane or in the extracellular space. Derlin proteins are a family of proteins that are conserved in all eukaryotes, where they function in ERAD. Here, we show that loss of Derlin function in Caenorhabditis elegans and in mouse macrophages results in the accumulation of integral membrane proteins at the plasma membrane. Induction of LDL receptor misfolding at the plasma membrane results in a sharp decrease in its half-life, which can be rescued by proteasomal inhibitors or by reduction of Derlin-1 levels. We also show that Derlin proteins localize to endosomes as well as to the ER. Our data are consistent with a model where Derlin proteins function in a spatially segregated quality control pathway that is used for the recognition and degradation of transmembrane proteins that become misfolded at the plasma membrane and/or in endosomes.

Original languageEnglish (US)
Pages (from-to)2228-2239
Number of pages12
JournalJournal of Cell Science
Volume122
Issue number13
DOIs
StatePublished - Jul 1 2009

Fingerprint

Membrane Proteins
Endoplasmic Reticulum-Associated Degradation
Proteins
Cell Membrane
Endosomes
Quality Control
LDL Receptors
Protein Folding
Caenorhabditis elegans
Extracellular Space
Proteasome Endopeptidase Complex
Ubiquitin
Eukaryota
Proteolysis
Half-Life
Cytoplasm
Macrophages
Enzymes

Keywords

  • Derlin
  • Membrane trafficking
  • Quality control

ASJC Scopus subject areas

  • Cell Biology

Cite this

Derlin-dependent accumulation of integral membrane proteins at cell surfaces. / Schaheen, Basil; Dang, Hope; Fares, Hanna F.

In: Journal of Cell Science, Vol. 122, No. 13, 01.07.2009, p. 2228-2239.

Research output: Contribution to journalArticle

Schaheen, Basil ; Dang, Hope ; Fares, Hanna F. / Derlin-dependent accumulation of integral membrane proteins at cell surfaces. In: Journal of Cell Science. 2009 ; Vol. 122, No. 13. pp. 2228-2239.
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