BAG-6 is essential for selective elimination of defective proteasomal substrates

Minami, Ryosuke; Hayakawa, Atsuko; Kagawa, Hiroyasu; Yanagi, Yuko; Yokosawa, Hideyoshi; Kawahara, Hiroyuki

doi:10.1083/jcb.200908092

Cited by 119 publications

(182 citation statements)

References 59 publications

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“…Knockdown of BAG6 had no influence on MHC class I cell surface expression indicating that loss of BAG6 can be effectively counterbalanced by other cytosolic chaperones under physiological conditions. This result is in contrast to a previous report by Minami et al (2010) who found reduced MHC class I cell surface expression in BAG6 knockdown cells (Minami et al, 2010) but in agreement with a more recent study by Koch and colleagues who did not find such an effect (Kamper et al, 2012). We have currently no explanation for this discrepancy, especially, since we could not detect any residual BAG6 expression after transfection with BAG6 siRNA.…”

Section: Discussionsupporting

confidence: 85%

“…In this study, we revisited the role of BAG6 in MHC class I antigen processing proposed by Minami et al (2010). However, we found no influence of BAG6 knockdown on MHC class I cell surface expression.…”

Section: Introductionmentioning

confidence: 75%

“…Although the DRiP hypothesis was postulated almost two decades ago there are still considerable gaps in the knowledge about antigen processing upstream of proteasomal degradation. Interestingly, a report by Minami et al (2010) found the chaperone BCL2-associated athanogene 6 (BAG6; also named Scythe or BAT3) to be essential for DRiP degradation and MHC class I cell surface expression (Minami et al, 2010). BAG6 is conserved in higher eukaryotes, ubiquitously expressed, and encoded in the MHC class III locus (Banerji et al, 1990;Ozaki et al, 1999;Wang and Liew, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…Even though BAG6 is clas-sified as a chaperone, it has no apparent folding activity (Wang et al, 2011). Together with its binding partners TRC35 and UBL4A it associates with long hydrophobic patches in client proteins and prevents aggregation (Leznicki et al, 2013;Mariappan et al, 2010;Minami et al, 2010;Wang et al, 2011). Therefore, BAG6 has also been described as a "holdase" which keeps its substrate in a soluble state (Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Bitzer

Basler

Groettrup

2016

Molecular Immunology

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a b s t r a c tAntigen processing for direct presentation on MHC class I molecules is a multistep process requiring the concerted activity of several cellular complexes. The essential steps at the beginning of this pathway, namely protein synthesis at the ribosome and degradation via the proteasome, have been known for years. Nevertheless, there is a considerable lack of factors identified to function between protein synthesis and degradation during antigen processing. Here, we analyzed the impact of the chaperone BAG6 on MHC class I cell surface expression and presentation of virus-derived peptides. Although an essential role of BAG6 in antigen processing has been proposed previously, we found BAG6 to be dispensable in this pathway. Still, interaction of BAG6 and the model antigen tyrosinase was enhanced during proteasome inhibition pointing towards a role of BAG6 in antigen degradation. Redundant chaperone pathways potentially mask the contribution of BAG6 to antigen processing and presentation.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Bitzer

Basler

Groettrup

2016

Molecular Immunology

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“…The N-terminal UBL domain of Bag6 connects the proteasome, where it interacts with RP non-ATPase 10c (29), with the ER, where it interacts with gp78 and ubiquitin regulatory X domaincontaining protein 8 (4,30). Downstream of this connection, the proline-rich domain has been implicated as the holdase domain binding to exposed hydrophobic regions and polyubiquitinated defective ribosomal products (4,23,54). Bag6 then acts as a scaffolding protein, simultaneously binding ubiquitylation machinery, the proteasome, TA-targeting factors, and proteins to be triaged.…”

Section: Discussionmentioning

confidence: 99%

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

Mock

Chartron

Zaslaver

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

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BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6–Ubl4A dimer demonstrates that Bag6–BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein α to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6.

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BAG6 deficiency induces mis‐distribution of mitochondrial clusters under depolarization

2019

Self Cite

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Accumulation of damaged mitochondria is implicated in a number of neurodegenerative disorders, including Parkinson's disease. Therefore, the machinery for mitochondrial quality control is important for the prevention of such diseases. It has been reported that Parkin‐ and p62/sequestosome 1 (SQSTM1)‐mediated clustering and subsequent elimination of damaged mitochondria (termed mitophagy) are critical for maintaining the quality of mitochondria under stress induced by uncoupling agents such as carbonyl cyanide m ‐chlorophenyl hydrazone. However, the molecular mechanisms underlying mitochondrial translocation to the perinuclear region during mitophagy have not been adequately addressed to date. In this study, we found that BCL2‐associated athanogene 6 (BAG6; also known as BAT3 or Scythe) is required for this process. Indeed, RNA interference‐mediated depletion of endogenous BAG6 prevented Parkin‐dependent relocalization of mitochondrial clusters to the perinuclear cytoplasmic region, whereas BAG6 knockdown did not affect the translocation of Parkin and p62/SQSTM1 to the depolarized mitochondria and subsequent aggregation. These results suggest that BAG6 is essential for cytoplasmic redistribution, but not for clustering, of damaged mitochondria.

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BAG-6 is essential for selective elimination of defective proteasomal substrates

Abstract: The ubiquitin-like protein BAG-6 protects cells from newly synthesized misfolded proteins by tethering them to the proteasome.

Cited by 119 publications

References 59 publications

Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

BAG6 deficiency induces mis‐distribution of mitochondrial clusters under depolarization

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