Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6

A portion of newly synthesized transmembrane domain proteins tend to fail to assemble correctly in the lumen of the endoplasmic reticulum, thus resulting in the production of a signal sequence-uncleaved form of the defective species. Although the efficient degradation of these mistargeted polypeptid...

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Bibliographic Details
Published in:Scientific reports 2017-11, Vol.7 (1), p.14545-13, Article 14545
Main Authors: Yamamoto, Koki, Hayashishita, Mizuki, Minami, Setsuya, Suzuki, Kanji, Hagiwara, Takumi, Noguchi, Aya, Kawahara, Hiroyuki
Format: Article
Language:English
Subjects:
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631/45/470/2284
631/45/474/2085
631/80/474/1768
82
82/1
82/29
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Cytoplasm
Efficiency
Endoplasmic reticulum
HeLa Cells
HLA-A Antigens - metabolism
Humanities and Social Sciences
Humans
Molecular Chaperones - metabolism
multidisciplinary
N-Terminus
Polypeptides
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Protein Sorting Signals
Proteins
Science
Science (multidisciplinary)
Solubilization
Species
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Summary:A portion of newly synthesized transmembrane domain proteins tend to fail to assemble correctly in the lumen of the endoplasmic reticulum, thus resulting in the production of a signal sequence-uncleaved form of the defective species. Although the efficient degradation of these mistargeted polypeptides is crucial, the molecular mechanism of their elimination pathway has not been adequately characterized. In this study, we focused on one such cryptic portion of a defective transmembrane domain protein, HLA-A, and show that a part of HLA-A is produced as a signal sequence-uncleaved labile species that is immediately targeted to the degradation pathway. We found that both BAG6 and proteasomes are indispensable for elimination of mislocalized HLA-A species. Furthermore, defective HLA-A is subjected to BAG6-dependent solubilization in the cytoplasm. These observations suggest that BAG6 acts as a critical factor for proteasome-mediated degradation of mislocalized HLA-A with a non-cleaved signal sequence at its N-terminus.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-14975-9