UBQLN4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation.
The majority of transmembrane proteins are integrated into the endoplasmic reticulum (ER) by virtue of a signal sequence-mediated co-translational process. However, a substantial portion of transmembrane proteins fails to reach the ER, leading to mislocalized cytosolic polypeptides. Their appropriate recognition and removal are of the utmost importance to avoid proteotoxic stress. Here, we identified UBQLN4 as a BAG6-binding factor that eliminates newly synthesized defective polypeptides. Using a truncated transmembrane domain protein whose degradation occurs during a pre-ER incorporation process as a model, we show that UBQLN4 recognizes misassembled proteins in the cytoplasm and targets these to the proteasome. We suggest that the exposed transmembrane segment of the defective polypeptides is essential for the UBQLN4-mediated substrate discrimination. Importantly, UBQLN4 recognizes not only the defective model substrate but also a pool of endogenous defective proteins that were induced by the depletion of the SRP54 subunit of the signal recognition particle. This study identifies a novel quality control mechanism for newly synthesized and defective transmembrane domain polypeptides that fail to reach their correct destination at the ER membrane.
Laboratory of Cell Biology and Biochemistry, Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan.
Rigel
R
Suzuki
Laboratory of Cell Biology and Biochemistry, Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan hkawa@tmu.ac.jp.
Hiroyuki
0000-0001-8506-9012
H
Kawahara
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D066329:Protein Aggregates; D011485:Protein Binding; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D059748:Proteolysis; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000378:metabolism; D018271:Signal Recognition Particle / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D002352:Carrier Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010455:Peptides; D066329:Protein Aggregates; D015375:Receptors, Interleukin-2; C480632:SRP54 protein, human; D018271:Signal Recognition Particle; C421907:UBQLN4 protein, human; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex
BAG6; SRP; proteasome; signal sequence; ubiquitin