UBQLN4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation. (22nd April 2016)

• Record Type: Journal Article
• Authors: Suzuki, Rigel; Kawahara, Hiroyuki
• Is Part Of: EMBO reports. Volume 17:Number 6(2016:Jun.)
• Page Start: 842
• Page End: 857
• Publication Date: 2016-04-22
• Subjects: BAG6 -- proteasome -- signal sequence -- SRP -- ubiquitin; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201541402
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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. Synopsis: This study shows that the BAG6‐binding factor UBQLN4 is essential for the elimination of mislocalized cytosolic transmembrane domain proteins that have failed to reach their correct destination at the ER membrane. UBQLN4 recognizes cytosolically mislocalized transmembrane proteins. UBQLN4 targets mislocalized proteins for proteasomal degradation. UBQLN4 also recognizes defective proteins induced by compromising the SRP. Abstract : This study shows that the BAG6‐binding factor UBQLN4 is essential for the elimination of mislocalized cytosolic transmembrane domain proteins that have failed to reach their correct destination at the ER membrane.