Cytoplasmic control of Rab family small
            <scp>GTP</scp>
            ases through
            <scp>BAG</scp>
            6

Takahashi, Tetsuya; Minami, Setsuya; Tsuchiya, Yugo; Tajima, Kazu; Sakai, Natsumi; Suga, Kei; Hisanaga, Shin‐ichi; Ohbayashi, Norihiko; Fukuda, Mitsunori; Kawahara, Hiroyuki

doi:10.15252/embr.201846794

Cited by 21 publications

(42 citation statements)

References 93 publications

(189 reference statements)

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“…Rodent CHO-K1 cells reportedly possess glucose incorporation systems (Hasegawa et al, 1990;Johnson et al, 1998), and glucose transporters provide a route for the entry of glucose into CHO-K1 cells (Hasegawa et al, 1990;Kanai et al, 1993;Wei et al, 1998;Johnson et al, 1998;Bogan et al, 2001;Selvi et al, 2010). Using this cell line, we recently showed that BAG6 plays critical roles in the appropriate trafficking of Golgi/endosomal proteins (Takahashi et al, 2019). During the course of our study, we noticed that the function of BAG6 might be linked with glucose uptake events in this cell line.…”

Section: Bag6 Deficiency Induces Partial Defects In Glucose Uptake Inmentioning

confidence: 50%

“…Previously, we reported that the intracellular localization of Patched1, a GLUT4-related 12 membrane-passed sterol transporter protein, is disturbed by Rab8a depletion (Takahashi et al, 2019). Furthermore, the endosomal localization of Patched1 in HeLa cells is impaired in BAG6-depleted cells (Takahashi et al, 2019).…”

Section: Bag6 Is Required For the Insulin-stimulated Relocation Of Inmentioning

confidence: 96%

“…Plasma membrane-localized glucose transporters are responsible for extracellular glucose incorporation into the cytoplasm (Huang and Czech, 2007;Bogan, 2012). Since Bag6 has been linked to potential obesity-and type 2 diabetes-associated loci (Kaminska et al, 2016;Carayol et al, 2017), and since BAG6 regulates the stability of the intrinsically unstable Rab8a-GDP-bound form (Takahashi et al, 2019), a small G protein that has been shown to be critical for insulin-stimulated GLUT4 sorting to the plasma membrane (Ishikura et al, 2007;Randhawa et al, 2008;Ishikura and Klip, 2008;Sun et al, 2010;Sadacca et al, 2013;Li et al, 2017), we were interested in examining the cell surface expression of GLUT4 (Rea and James, 1997;Li et al, 2009;Leto and Saltiel, 2012). To investigate this point, we established a series of CHO-K1 cell lines that were stably co-transfected with Glut4 as well as insulin receptor (IR) genes ( Fig.…”

Section: Establishment Of Transgenic Cell Lines Expressing Glut4 Withmentioning

confidence: 99%

“…Since BAG6 was also suggested as a component of the TA protein membrane assembly machinery (Mariappan et al, 2010;Leznicki et al, 2010;Hegde and Keenan, 2011;Casson et al, 2017;Shao et al, 2017) and since Stx6 is a TA protein whose dysfunction affects the cell surface expression of GLUT4 (Fig. 6A), we suspected that the observed GLUT4 trafficking defects under BAG6 depletion might partly be due to a failure in Stx6 function, in addition to the misregulation of Rab8a (Takahashi et al, 2019). Therefore, we examined whether Stx6 was synthesized properly under BAG6 depletion.…”

Section: Bag6 Has a Partial Role In The Membrane Integration Of Stx6mentioning

confidence: 99%

“…BAG6 protein possesses an intrinsic affinity for the exposed hydrophobicity of its client proteins in the cytosol, and escorts them to the degradation machinery (Kikukawa et al, 2005;Minami et al, 2010;Hessa et al, 2011;Wang et al, 2011;Lee and Ye, 2013;Suzuki and Kawahara, 2016;Tanaka et al, 2016;Guna and Hegde, 2018). BAG6 also recognizes the hydrophobic residues of Rab8a, which are specifically exposed in its GDP-bound form (Takahashi et al, 2019). This interaction stimulates the degradation of Rab8a (GDP), whose accumulation impairs Rab8a-mediated intracellular membrane trafficking.…”

Section: Introductionmentioning

confidence: 99%

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BAG6 contributes to glucose uptake by supporting the cell surface translocation of the glucose transporter GLUT4

2020

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Defective translocation of glucose transporter 4 (GLUT4) to the cell surface is a key feature of insulin resistance in type 2 diabetes. Therefore, elucidating the mechanism of GLUT4 translocation is of primary importance. The mammalian Bag6/Bat3 gene has been suggested to be linked with potential obesity-and diabetes-associated loci, while its function in the control of glucose incorporation into the cytoplasm has not been investigated. In this study, we established a series of cell lines that stably expressed GLUT4 with three tandem repeats of the antigenic peptide inserted into its 1st extracellular loop. With these cell lines, we found that the depletion of endogenous BAG6 downregulated the cell surface expression of GLUT4, concomitant with the reduced incorporation of a glucose analog into the cells. Defective intracellular translocation of GLUT4 in BAG6-depleted cells is similar to the case observed for the depletion of Rab8a, an essential regulator of insulin-stimulated GLUT4 translocation. In addition, we observed that the assembly of syntaxin 6 into the endoplasmic reticulum membrane was slightly disturbed under BAG6 depletion. Given that Rab8a and syntaxin 6 are critical for GLUT4 translocation, we suggest that BAG6 may play multiple roles in the trafficking of glucose transporters to the cell surface. This article has an associated First Person interview with the first author of the paper.

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Section: Bag6 Deficiency Induces Partial Defects In Glucose Uptake Inmentioning

confidence: 50%

Section: Bag6 Is Required For the Insulin-stimulated Relocation Of Inmentioning

confidence: 96%

Section: Establishment Of Transgenic Cell Lines Expressing Glut4 Withmentioning

confidence: 99%

Section: Bag6 Has a Partial Role In The Membrane Integration Of Stx6mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BAG6 contributes to glucose uptake by supporting the cell surface translocation of the glucose transporter GLUT4

2020

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Mutations in GET4 disrupt the transmembrane domain recognition complex pathway

Tambe

Shimada

et al. 2020

J of Inher Metab Disea

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The transmembrane domain recognition complex (TRC) targets cytoplasmic C‐terminal tail‐anchored (TA) proteins to their respective membranes in the endoplasmic reticulum (ER), Golgi, and mitochondria. It is composed of three proteins, GET4, BAG6, and GET5. We identified an individual with compound heterozygous missense variants (p.Arg122His, p.Ile279Met) in GET4 that reduced all three TRC proteins by 70% to 90% in his fibroblasts, suggesting a possible defect in TA protein targeting. He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism, and delayed bone age. We found the TA protein, syntaxin 5, is poorly targeted to Golgi membranes compared to normal controls. Since GET4 regulates ER to Golgi transport, we hypothesized that such transport would be disrupted in his fibroblasts, and discovered that retrograde (but not anterograde) transport was significantly reduced. Despite reduction in the three TRC proteins, their mRNA levels were unchanged, suggesting increased degradation in patient fibroblasts. Treating fibroblasts with the FDA‐approved proteasome inhibitor, bortezomib (10 nM), restored syntaxin 5 localization and nearly normalized the levels of all three TRC proteins. Our study identifies the first individual with GET4 mutations.

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