Cytoplasmic control of Rab family small GTPases through BAG6. (25th February 2019)

• Record Type: Journal Article
• Authors: Takahashi, Toshiki; Minami, Setsuya; Tsuchiya, Yugo; Tajima, Kazu; Sakai, Natsumi; Suga, Kei; Hisanaga, Shin‐ichi; Ohbayashi, Norihiko; Fukuda, Mitsunori; Kawahara, Hiroyuki
• Is Part Of: EMBO reports. Volume 20:Number 4(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-02-25
• Subjects: BAG6 -- membrane trafficking -- Rab GTP‐binding proteins -- Rab8a -- ubiquitin‐proteasome system; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201846794
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Rab family small GTPases are master regulators of distinct steps of intracellular vesicle trafficking in eukaryotic cells. GDP‐bound cytoplasmic forms of Rab proteins are prone to aggregation due to the exposure of hydrophobic groups but the machinery that determines the fate of Rab species in the cytosol has not been elucidated in detail. In this study, we find that BAG6 (BAT3/Scythe) predominantly recognizes a cryptic portion of GDP‐associated Rab8a, while its major GTP‐bound active form is not recognized. The hydrophobic residues of the Switch I region of Rab8a are essential for its interaction with BAG6 and the degradation of GDP‐Rab8a via the ubiquitin‐proteasome system. BAG6 prevents the excess accumulation of inactive Rab8a, whose accumulation impairs intracellular membrane trafficking. BAG6 binds not only Rab8a but also a functionally distinct set of Rab family proteins, and is also required for the correct distribution of Golgi and endosomal markers. From these observations, we suggest that Rab proteins represent a novel set of substrates for BAG6, and the BAG6‐mediated pathway is associated with the regulation of membrane vesicle trafficking events in mammalian cells. Synopsis: BAG6 specifically recognizes exposed hydrophobic residues in the Switch I region of inactive, GDP‐bound Rab8a. BAG6 targets GDP‐Rab8a to proteasomal degradation to maintain the integrity of the Golgi and endosomal compartments. BAG6 is required for the correct distribution of Golgi/endosomal markers. BAG6 recognizes the GDP‐bound form of Rab8a for ubiquitin‐mediated degradation. The hydrophobicity of the Switch I region is essential for the instability of Rab8a. Abstract : BAG6 specifically recognizes exposed hydrophobic residues in the Switch I region of inactive, GDP‐bound Rab8a. BAG6 targets GDP‐Rab8a to proteasomal degradation to maintain the integrity of the Golgi and endosomal compartments.