The yeast ERAD-C ubiquitin ligase Doa10 recognizes an intramembrane degron.
Aberrant endoplasmic reticulum (ER) proteins are eliminated by ER-associated degradation (ERAD). This process involves protein retrotranslocation into the cytosol, ubiquitylation, and proteasomal degradation. ERAD substrates are classified into three categories based on the location of their degradation signal/degron: ERAD-L (lumen), ERAD-M (membrane), and ERAD-C (cytosol) substrates. In Saccharomyces cerevisiae, the membrane proteins Hrd1 and Doa10 are the predominant ERAD ubiquitin-protein ligases (E3s). The current notion is that ERAD-L and ERAD-M substrates are exclusively handled by Hrd1, whereas ERAD-C substrates are recognized by Doa10. In this paper, we identify the transmembrane (TM) protein Sec61 β-subunit homologue 2 (Sbh2) as a Doa10 substrate. Sbh2 is part of the trimeric Ssh1 complex involved in protein translocation. Unassembled Sbh2 is rapidly degraded in a Doa10-dependent manner. Intriguingly, the degron maps to the Sbh2 TM region. Thus, in contrast to the prevailing view, Doa10 (and presumably its human orthologue) has the capacity for recognizing intramembrane degrons, expanding its spectrum of substrates.
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Gregor
G
Habeck
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Felix A
FA
Ebner
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Hiroko
H
Shimada-Kreft
Department of Biology, University of Konstanz, 78457 Konstanz, Germany stefan.kreft@uni-konstanz.de.
Stefan G
SG
Kreft
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D006801:Humans; D015151:Immunoblotting; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D021381:Protein Transport; D000069816:SEC Translocation Channels; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D026901:Membrane Transport Proteins; C101189:SBH2 protein, S cerevisiae; D000069816:SEC Translocation Channels; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C091362:SSM4 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases