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UBQLN 4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation
Author(s) -
Suzuki Rigel,
Kawahara Hiroyuki
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201541402
Subject(s) - transmembrane domain , endoplasmic reticulum , transmembrane protein , microbiology and biotechnology , cytoplasm , signal recognition particle , signal peptide , endoplasmic reticulum associated protein degradation , membrane protein , cytosol , protein subunit , proteostasis , protein sorting signals , proteasome , biology , chemistry , biochemistry , peptide sequence , unfolded protein response , membrane , enzyme , receptor , gene
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 UBQLN 4 as a BAG 6‐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 UBQLN 4 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 UBQLN 4‐mediated substrate discrimination. Importantly, UBQLN 4 recognizes not only the defective model substrate but also a pool of endogenous defective proteins that were induced by the depletion of the SRP 54 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.