Ubiquitin-Dependent Intramembrane Rhomboid Protease Promotes ERAD of Membrane Proteins

• Published in: Molecular cell Vol. 47; no. 4; pp. 558 - 569
• Main Authors: Fleig, Lina, Bergbold, Nina, Sahasrabudhe, Priyanka, Geiger, Beate, Kaltak, Lejla, Lemberg, Marius K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.08.2012
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Amino Acid Sequence; Cells, Cultured; cytosol; Cytosol - metabolism; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum-Associated Degradation - genetics; Endoplasmic Reticulum-Associated Degradation - physiology; HEK293 Cells; Humans; membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Peptide Hydrolases - genetics; Peptide Hydrolases - metabolism; Phylogeny; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein Structure, Tertiary; Protein Transport; proteinases; Proteolysis; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Stress, Physiological - genetics; Stress, Physiological - physiology; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.06.008

The ER-associated degradation (ERAD) pathway serves as an important cellular safeguard by directing incorrectly folded and unassembled proteins from the ER to the proteasome. Still, however, little is known about the components mediating ERAD of membrane proteins. Here we show that the evolutionary conserved rhomboid family protein RHBDL4 is a ubiquitin-dependent ER-resident intramembrane protease that is upregulated upon ER stress. RHBDL4 cleaves single-spanning and polytopic membrane proteins with unstable transmembrane helices, leading to their degradation by the canonical ERAD machinery. RHBDL4 specifically binds the AAA+-ATPase p97, suggesting that proteolytic processing and dislocation into the cytosol are functionally linked. The phylogenetic relationship between rhomboids and the ERAD factor derlin suggests that substrates for intramembrane proteolysis and protein dislocation are recruited by a shared mechanism. [Display omitted] ► Intramembrane rhomboid protease RHBDL4 cleaves ubiquitinated ERAD substrates ► Substrates are cleaved within transmembrane helices and luminal domains ► Recognition of ubiquitin and p97-binding link RHBDL4 to the canonical ERAD pathway ► RHBDL4 plays an essential role in the control of ER protein homeostasis