Alternative titles; symbols
HGNC Approved Gene Symbol: BAG6
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38) : 6:31,639,028-31,652,661 (from NCBI)
By chromosome walking with overlapping cosmids, Spies et al. (1989) isolated a 435-kb DNA segment that was centromeric to HLA-B (142830) in the human major histocompatibility complex. The presence of additional genes was suggested by a large cluster of CpG islands. With cosmid probes, 5 distinct transcripts, including BAT3, were detected in RNA samples from a variety of cell lines, and the corresponding cDNA clones were isolated.
From cDNA clones, Banerji et al. (1990) determined the complete sequences of the closely linked BAT2 (142580) and BAT3 genes. The putative proteins are 228 and 110 kD, respectively. BAT3 contains an N-terminal ubiquitin-like domain, and both BAT2 and BAT3 are rich in proline and include short tracts of polyproline, polyglycine, and charged amino acids.
Sasaki et al. (2007) showed that depletion of BAT3 from human and mouse cells impaired p53 (TP53; 191170)-mediated transactivation of its target genes Puma (BBC3; 605854) and p21 (CDKN1A; 116899). Although DNA damage-induced phosphorylation, stabilization, and nuclear accumulation of p53 were not significantly affected by BAT3 depletion, p53 acetylation was almost completely abolished. BAT3 formed a complex with p300 (EP300; 602700), and an increased amount of BAT3 enhanced recruitment of p53 to p300 and facilitated subsequent p53 acetylation. In contrast, Bat3-depleted cells showed reduced p53-p300 complex formation and decreased p53 acetylation. Thymocytes from Bat3-deficient mice exhibited reduced p53-mediated induction of Puma and p21 and were resistant to DNA damage-induced apoptosis in vivo. Sasaki et al. (2007) concluded that BAT3 is an essential regulator of p53-mediated responses to genotoxic stress, and that BAT3 controls DNA damage-induced acetylation of p53.
Mariappan et al. (2010) identified a conserved 3-protein complex composed of BAT3, TRC35 (612056), and UBL4A (312070) that facilitates tail-anchored protein capture by TRC40 (601913). This BAT3 complex is recruited to ribosomes synthesizing membrane proteins, interacts with the transmembrane domains of newly released tail-anchored proteins, and transfers them to TRC40 for targeting. Depletion of the BAT3 complex allows non-TRC40 factors to compete for tail-anchored proteins, explaining their mislocalization in the analogous yeast deletion strains. Thus, the BAT3 complex acts as a TMD-selective chaperone that effectively channels tail-anchored proteins to the TRC40 insertion pathway.
Hessa et al. (2011) reconstituted mislocalized protein degradation in vitro to identify factors involved in the pathway and found that nascent membrane proteins tethered to ribosomes are not substrates for ubiquitination unless they are released into the cytosol. Their inappropriate release results in capture by the BAG6 complex, a ribosome-associating chaperone. BAG6 complex-mediated capture depends on the presence of unprocessed or noninserted hydrophobic domains that distinguish mislocalized proteins from potential cytosolic proteins. A subset of these BAG6 complex 'clients' are transferred to TRC40 for insertion into the membrane, whereas the remainder are rapidly ubiquitinated. Depletion of the BAG6 complex selectively impairs the efficient ubiquitination of mislocalized proteins. Thus, Hessa et al. (2011) concluded that by its presence on ribosomes that are synthesizing nascent membrane proteins, the BAG6 complex links targeting and ubiquitination pathways. The authors proposed that such coupling allows the fast tracking of mislocalized proteins for degradation without futile engagement of the cytosolic folding machinery.
To understand how the fate of nascent tail-anchored membrane proteins is determined, Shao et al. (2017) reconstituted the core reactions for membrane targeting and ubiquitination of these proteins. They found that the central 6-component triage system is divided into an uncommitted client-SGTA (603419) complex, a self-sufficient targeting module, and an embedded but self-sufficient quality control module. Client-SGTA engagement of the targeting module induced rapid, private, and committed client transfer to TRC40 (601913) for successful biosynthesis. Commitment to ubiquitination is dictated primarily by comparatively slower client dissociation from SGTA and nonprivate capture by the BAG6 subunit of the quality control module. Shao et al. (2017) concluded that their results provided a paradigm for how priority and time are encoded within a multichaperone triage system.
Spies et al. (1989) mapped the BAG6 (BAT3) gene to chromosome 6p21.
Sasaki et al. (2007) found that embryonic lethality of Bat3 deletion in mice was dependent on genetic background.
Banerji, J., Sands, J., Strominger, J. L., Spies, T. A gene pair from the human major histocompatibility complex encodes large proline-rich proteins with multiple repeated motifs and a single ubiquitin-like domain. Proc. Nat. Acad. Sci. 87: 2374-2378, 1990. [PubMed: 2156268] [Full Text: https://doi.org/10.1073/pnas.87.6.2374]
Hessa, T., Sharma, A., Mariappan, M., Eshleman, H. D., Gutierrez, E., Hegde, R. S. Protein targeting and degradation are coupled for elimination of mislocalized proteins. Nature 475: 394-397, 2011. [PubMed: 21743475] [Full Text: https://doi.org/10.1038/nature10181]
Mariappan, M., Li, X., Stefanovic, S., Sharma, A., Mateja, A., Keenan, R. J., Hegde, R. S. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature 466: 1120-1124, 2010. [PubMed: 20676083] [Full Text: https://doi.org/10.1038/nature09296]
Sasaki, T., Gan, E. C., Wakeham, A., Kornbluth, S., Mak, T. W., Okada, H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 21: 848-861, 2007. [PubMed: 17403783] [Full Text: https://doi.org/10.1101/gad.1534107]
Shao, S., Rodrigo-Brenni, M. C., Kivlen, M. H., Hegde, R. S. Mechanistic basis for a molecular triage reaction. Science 355: 298-302, 2017. [PubMed: 28104892] [Full Text: https://doi.org/10.1126/science.aah6130]
Spies, T., Blanck, G., Bresnahan, M., Sands, J., Strominger, J. L. A new cluster of genes within the human major histocompatibility complex. Science 243: 214-217, 1989. [PubMed: 2911734] [Full Text: https://doi.org/10.1126/science.2911734]