Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins

Lina Fleig; Nina Bergbold; Priyanka Sahasrabudhe; Beate Geiger; Lejla Kaltak; Marius K Lemberg

doi:10.1016/j.molcel.2012.06.008

Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins

Mol Cell. 2012 Aug 24;47(4):558-69. doi: 10.1016/j.molcel.2012.06.008. Epub 2012 Jul 12.

Authors

Lina Fleig¹, Nina Bergbold, Priyanka Sahasrabudhe, Beate Geiger, Lejla Kaltak, Marius K Lemberg

Affiliation

¹ Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.

PMID: 22795130
DOI: 10.1016/j.molcel.2012.06.008

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism
Amino Acid Sequence
Cells, Cultured
Cytosol / metabolism
Endoplasmic Reticulum / genetics
Endoplasmic Reticulum / metabolism*
Endoplasmic Reticulum-Associated Degradation / genetics
Endoplasmic Reticulum-Associated Degradation / physiology*
HEK293 Cells
Humans
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 / metabolism
Protein Binding
Protein Structure, Tertiary
Protein Transport
Proteolysis
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / metabolism
Stress, Physiological / genetics
Stress, Physiological / physiology
Ubiquitin / genetics
Ubiquitin / metabolism*

Substances

Membrane Proteins
Nuclear Proteins
Receptors, Antigen, T-Cell
Ubiquitin
Peptide Hydrolases
RHBDL3 protein, human
Proteasome Endopeptidase Complex
Adenosine Triphosphatases
p97 ATPase