BAG6

Summary

BAG6 (BAG cochaperone 6, HGNC:13919) is a protein-coding gene on chromosome 6p21.33, encoding Large proline-rich protein BAG6 (P46379). ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins.

This gene was first characterized as part of a cluster of genes located within the human major histocompatibility complex class III region. This gene encodes a nuclear protein that is cleaved by caspase 3 and is implicated in the control of apoptosis. In addition, the protein forms a complex with E1A binding protein p300 and is required for the acetylation of p53 in response to DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7917 — RefSeq curated summary.

At a glance

• GWAS associations: 47
• Clinical variants (ClinVar): 158 total
• Druggable target: yes
• MANE Select transcript: NM_001387994

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13919
Approved symbol	BAG6
Name	BAG cochaperone 6
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	G3, D6S52E, Scythe
Ensembl gene	ENSG00000204463
Ensembl biotype	protein_coding
OMIM	142590
Entrez	7917

Gene structure

Transcript identifiers

Ensembl transcripts: 112 — 102 protein_coding, 6 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000211379, ENST00000362049, ENST00000375964, ENST00000375976, ENST00000422948, ENST00000424176, ENST00000424480, ENST00000428326, ENST00000433828, ENST00000434444, ENST00000435080, ENST00000437771, ENST00000438149, ENST00000439687, ENST00000441054, ENST00000441793, ENST00000451898, ENST00000452994, ENST00000453833, ENST00000454165, ENST00000456286, ENST00000456622, ENST00000462682, ENST00000462875, ENST00000464126, ENST00000464869, ENST00000465348, ENST00000469182, ENST00000470875, ENST00000676571, ENST00000676615, ENST00000678272, ENST00000679119, ENST00000888810, ENST00000888811, ENST00000888812, ENST00000888813, ENST00000888814, ENST00000888815, ENST00000888816, ENST00000888817, ENST00000888818, ENST00000888819, ENST00000888820, ENST00000888821, ENST00000888822, ENST00000888823, ENST00000888824, ENST00000888825, ENST00000888826, ENST00000888827, ENST00000888828, ENST00000888829, ENST00000888830, ENST00000888831, ENST00000888832, ENST00000888833, ENST00000888834, ENST00000888835, ENST00000888836, ENST00000888837, ENST00000888838, ENST00000888839, ENST00000888840, ENST00000888841, ENST00000888842, ENST00000888843, ENST00000888844, ENST00000888845, ENST00000888846, ENST00000888847, ENST00000888848, ENST00000888849, ENST00000888850, ENST00000888851, ENST00000888852, ENST00000888853, ENST00000888854, ENST00000888855, ENST00000888856, ENST00000888857, ENST00000888858, ENST00000888859, ENST00000888860, ENST00000888861, ENST00000888862, ENST00000888863, ENST00000888864, ENST00000888865, ENST00000888866, ENST00000888867, ENST00000888868, ENST00000921978, ENST00000921979, ENST00000921980, ENST00000921981, ENST00000921982, ENST00000921983, ENST00000921984, ENST00000921985, ENST00000921986, ENST00000921987, ENST00000921988, ENST00000960797, ENST00000960798, ENST00000960799, ENST00000960800, ENST00000960801, ENST00000960802, ENST00000960803, ENST00000960804, ENST00000960805

RefSeq mRNA: 59 — MANE Select: NM_001387994 NM_001098534, NM_001199697, NM_001199698, NM_001387940, NM_001387942, NM_001387943, NM_001387944, NM_001387946, NM_001387949, NM_001387951, NM_001387954, NM_001387955, NM_001387956, NM_001387958, NM_001387961, NM_001387963, NM_001387964, NM_001387965, NM_001387982, NM_001387983, NM_001387984, NM_001387985, NM_001387986, NM_001387987, NM_001387988, NM_001387989, NM_001387990, NM_001387991, NM_001387992, NM_001387993, NM_001387994, NM_001387995, NM_001387996, NM_001387997, NM_001387998, NM_001387999, NM_001388000, NM_001388001, NM_001388002, NM_001388003, NM_001388004, NM_001388005, NM_001388006, NM_001388007, NM_001388008, NM_001388009, NM_001388010, NM_001388011, NM_001388012, NM_001388013, NM_001388014, NM_001388015, NM_001388016, NM_001388017, NM_001388018, NM_001388019, NM_001388020, NM_080702, NM_080703

CCDS: CCDS4709, CCDS56414, CCDS56415, CCDS93881, CCDS93882

Canonical transcript exons

ENST00000383448 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 99.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 83.8469 / max 652.2689, expressed in 1824 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72770	65.6357	1822
72765	3.2843	1493
72769	3.2625	1448
72771	3.2515	1589
72766	1.8191	1114
72768	1.7738	1184
72764	1.3920	871
72767	1.3842	984
72758	1.0998	731
72761	0.5020	273

Top tissues by expression

144 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	99.49	gold quality
left testis	UBERON:0004533	99.48	gold quality
testis	UBERON:0000473	98.82	gold quality
right lobe of thyroid gland	UBERON:0001119	98.77	gold quality
right uterine tube	UBERON:0001302	98.76	gold quality
apex of heart	UBERON:0002098	98.75	gold quality
cortical plate	UBERON:0005343	98.69	gold quality
pituitary gland	UBERON:0000007	98.63	gold quality
ganglionic eminence	UBERON:0004023	98.61	gold quality
embryo	UBERON:0000922	98.60	gold quality
left lobe of thyroid gland	UBERON:0001120	98.60	gold quality
adenohypophysis	UBERON:0002196	98.56	gold quality
thyroid gland	UBERON:0002046	98.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.51	gold quality
lower esophagus mucosa	UBERON:0035834	98.50	gold quality
gastrocnemius	UBERON:0001388	98.46	gold quality
spleen	UBERON:0002106	98.45	gold quality
endocervix	UBERON:0000458	98.43	gold quality
granulocyte	CL:0000094	98.38	gold quality
prostate gland	UBERON:0002367	98.38	gold quality
heart left ventricle	UBERON:0002084	98.33	gold quality
metanephros cortex	UBERON:0010533	98.32	gold quality
fundus of stomach	UBERON:0001160	98.28	gold quality
ventricular zone	UBERON:0003053	98.27	gold quality
skeletal muscle tissue	UBERON:0001134	98.24	gold quality
skin of leg	UBERON:0001511	98.24	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.24	gold quality
right ovary	UBERON:0002118	98.23	gold quality
cortex of kidney	UBERON:0001225	98.21	gold quality
left ovary	UBERON:0002119	98.21	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.21
E-MTAB-7303	no	92.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CXXC1, TBX2, TBXT, TCF3, TP53

miRNA regulators (miRDB)

6 targeting BAG6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-4693-5P	97.35	67.02	1234
HSA-MIR-6895-5P	97.05	64.96	522
HSA-MIR-6508-3P	96.73	65.48	576

Literature-anchored findings (GeneRIF, showing 40)

• Evidence indicates that casp3 activated by ricin acts on BAT3 at the caspase cleavage site, DEQD(1001) to release a C-terminal fragment designated CTF-131, which induces phosphatidylserine exposure, cell rounding, and chromatin condensation as ricin does (PMID:14960581)
• Interaction of hSGT with Hsc70, Hsp70 or Bag-6/Bat-3/Scythe was demonstrated in prometaphase, thereby suggesting a possible role for complexes containing hSGT and distinct (co)-chaperones during mitosis. (PMID:16777091)
• MRK phosphorylates Scythe at T1080 in vitro as determined by site-directed mutagenesis and mass spectrometry, supporting the consensus and suggesting Scythe as a physiological substrate for MRK. (PMID:16954377)
• Bat3 is a novel and essential regulator of p53-mediated responses to genotoxic stress, and that Bat3 controls DNA damage-induced acetylation of p53. (PMID:17403783)
• occurrence of an unusual TG 3’ splice site in intron 6 (PMID:17672918)
• HLA-B-associated transcript 3 (BAT3) was released from tumor cells, bound directly to NKp30, and engaged NKp30 on NK cells. BAT3 triggered NKp30-mediated cytotoxicity and was necessary for tumor rejection in a multiple myeloma model. (PMID:18055229)
• Scythe regulates apoptosis-inducing factor stability during endoplasmic reticulum stress-induced apoptosis (PMID:18056262)
• BORIS acts as a platform upon which BAT3 and SET1A assemble and exert effects upon chromatin structure and gene expression. (PMID:18765639)
• NKp30-mediated NK cells/dendritic cells cross talk resulting either in iDC killing or maturation was BAT3-dependent (PMID:18852879)
• colocalization of PBF and Scythe/BAT3 in the nucleus might be an important factor for survival of osteosarcoma cells. (PMID:19018758)
• The HSP70-driven degradation of BAG6, following the BAG6-dependent accumulation of HSP70, could allow the protein-refolding activity of HSP70 and limit the extent of its induction. (PMID:19357808)
• Results suggest BAT2 -8671, BAT3 8854, and BAT5 22655, 9569 SNPs as well as BAT haplotypes (ATTGTG and ATCATG) might be associated with higher Kawasaki disease susceptibility and coronary artery aneurysm formation. (PMID:20626023)
• Data suggest that BAG-6 is necessary for ubiquitin-mediated degradation of newly synthesized defective polypeptides. (PMID:20713601)
• We present a mechanism explaining how parallel IFNgamma-mediated regulation of CIITA and of its chaperone BAT3 controls the level of components of the HLA class II processing pathway. (PMID:21940994)
• BAT3, a cytosolic chaperone, is recruited to the site of dislocation through its interaction with Derlin2. (PMID:22174835)
• Data show that cleavage of Scythe by caspase-3 occurs after activation of both the extrinsic (i.e. Fas/APO-1-mediated) and the intrinsic (i.e. staurosporine-induced) apoptosis pathway. (PMID:22285488)
• These findings identify a novel role for Bat3 in regulating DOT1L function, which plays a critical role in DNA damage response. (PMID:22373577)
• Cell type-specific subcellular expression of BAT3 suggests distinct functions in the cytosol and in the nucleus. (PMID:22558287)
• Aberrant enhancement of YWK-II/APLP2 by nuclear export of Bat3 may play a role in cancer development by inhibiting cell apoptosis. (PMID:22641691)
• Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. (PMID:22863785)
• our results suggest an essential role for AIF and its binding partner Scythe in the pathway leading to apoptotic corpse clearance. (PMID:23077592)
• A BAG6/SGTA cycle operates during protein maturation and quality control in the cytosol. (PMID:23129660)
• SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation. (PMID:23246001)
• Data indicate that the Bag6-Ubl4A-Trc35 complex is localized to the endoplasmic reticulum (ER) membrane to regulate ER-associated degradation (ERAD). (PMID:23665563)
• Data indicate that BCL2-associated athanogene 6 (BAG6) appears to be the central component for the process, as depletion of BAG6 leads to the loss of both UBL4A and GET4 proteins and resistance to cell killing by DNA-damaging agents. (PMID:23723067)
• Bag6, a protein in the TRC pathway that is also responsible for the degradation of mislocalized proteins, is not only involved in core particle assembly but also has a key role in efficient regulatory particle assembly. (PMID:23900548)
• we show for the first time that BAG-6(686-936) comprises a subdomain of BAG-6, which is sufficient for receptor docking and inhibition of NKp30-dependent NK cell cytotoxicity as part of a tumor immune escape mechanism (PMID:24133212)
• show that endogenous dislocation clients are captured specifically in association with the cytosolic chaperone BAG6, or retrieved en masse via their glycan handle (PMID:24594942)
• VNTR in the coding region of the FAM46A gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP are associated with susceptibility to tuberculosis (PMID:24625963)
• Exogenous BAG6 perturbs the function of the BAG6 complex at a stage subsequent to substrate recognition and polyubiquitylation, most likely the BAG6-dependent delivery of OpD to the proteasome. (PMID:24806960)
• RNF126 is recruited to the N-terminal Ubl domain of Bag6 and preferentially ubiquitinates juxtahydrophobic lysine residues on Bag6-associated clients. (PMID:24981174)
• This meta-analysis suggested that BAT3 polymorphisms contributed the development of lung cancer. (PMID:24989925)
• Tim-3/Gal-9 interaction favors apoptosis of MBP-specific T lymphocytes in benign multiple sclerosis; this process is reduced in PPMS by the up-regulation of Bat3 (PMID:25091272)
• The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT. (PMID:25111513)
• Susceptibility to large-joint osteoarthritis (hip and knee) is associated with BAG6 rs3117582 SNP and the VNTR polymorphism in the second exon of the FAM46A gene on chromosome 6. (PMID:25231575)
• Data show that molecular chaperone BAG6_ubiquitin-like domain (UBL) and ubiquitin-like 4A UBL4A_UBL compete for the same binding site on N-terminal dimerisation domain of SGTA protein (SGTA_NT). (PMID:25415308)
• This meta-analysis suggested that HLA-B-associated transcript 3 polymorphisms are risk factors for lung cancer. (PMID:25430685)
• Both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. (PMID:25535373)
• BAG6 rs3117582 SNP was associated with non small cell lung cancer in the Norwegian subjects and the combined Croatian-Norwegian subjects corroborating the earlier finding that BAG6 rs3117582 SNP was associated with lung cancer in Europeans. (PMID:25884493)
• BAG6 co-localizes with HSPA2 in huinan testicular germ cells and epididymal spermatozoa, moving from the equator to the anterior head during capacitation and stably interacting with HSPA2. In zona pellucida binding defect infertility, BAG6 is lacking. (PMID:26153132)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	bag6	ENSDARG00000075892
danio_rerio	bag6l	ENSDARG00000077531
mus_musculus	Bag6	ENSMUSG00000024392
rattus_norvegicus	Bag6	ENSRNOG00000000851
drosophila_melanogaster	CG7546	FBGN0035793
caenorhabditis_elegans		WBGENE00022800

Protein

Protein identifiers

Large proline-rich protein BAG6 — P46379 (reviewed: P46379)

Alternative names: BAG family molecular chaperone regulator 6, BCL2-associated athanogene 6, HLA-B-associated transcript 3, Protein G3, Protein Scythe

All UniProt accessions (19): P46379, A0A1B0GX79, A0A1U9X7A6, A0A7I2V3H1, A0A7I2V508, A0A7P0MQS5, F6S6P2, F6TC96, F6U1F2, F6U341, F6UR09, F6VEM6, F6WML8, F6X9W3, F6XTU0, H0Y4L1, H0Y759, H0Y7K4, X6REW1

UniProt curated annotations — full annotation on UniProt →

Function. ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins. Functions as part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, which maintains these client proteins in a soluble state and participates in their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation. The BAG6/BAT3 complex is involved in the post-translational delivery of tail-anchored/type II transmembrane proteins to the endoplasmic reticulum membrane. Recruited to ribosomes, it interacts with the transmembrane region of newly synthesized tail-anchored proteins and together with SGTA and ASNA1 mediates their delivery to the endoplasmic reticulum. Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated by RNF126, an E3 ubiquitin-protein ligase associated with BAG6 and are sorted to the proteasome. SGTA which prevents the recruitment of RNF126 to BAG6 may negatively regulate the ubiquitination and the proteasomal degradation of client proteins. Similarly, the BAG6/BAT3 complex also functions as a sorting platform for proteins of the secretory pathway that are mislocalized to the cytosol either delivering them to the proteasome for degradation or to the endoplasmic reticulum. The BAG6/BAT3 complex also plays a role in the endoplasmic reticulum-associated degradation (ERAD), a quality control mechanism that eliminates unwanted proteins of the endoplasmic reticulum through their retrotranslocation to the cytosol and their targeting to the proteasome. It maintains these retrotranslocated proteins in an unfolded yet soluble state condition in the cytosol to ensure their proper delivery to the proteasome. BAG6 is also required for selective ubiquitin-mediated degradation of defective nascent chain polypeptides by the proteasome. In this context, it may participate in the production of antigenic peptides and play a role in antigen presentation in immune response. BAG6 is also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. BAG6 may ensure the proper degradation of these proteins and thereby protects the endoplasmic reticulum from protein overload upon stress. By inhibiting the polyubiquitination and subsequent proteasomal degradation of HSPA2 it may also play a role in the assembly of the synaptonemal complex during spermatogenesis. Also positively regulates apoptosis by interacting with and stabilizing the proapoptotic factor AIFM1. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway. Involved in DNA damage-induced apoptosis: following DNA damage, accumulates in the nucleus and forms a complex with p300/EP300, enhancing p300/EP300-mediated p53/TP53 acetylation leading to increase p53/TP53 transcriptional activity. When nuclear, may also act as a component of some chromatin regulator complex that regulates histone 3 ‘Lys-4’ dimethylation (H3K4me2). Released extracellularly via exosomes, it is a ligand of the natural killer/NK cells receptor NCR3 and stimulates NK cells cytotoxicity. It may thereby trigger NK cells cytotoxicity against neighboring tumor cells and immature myeloid dendritic cells (DC). Mediates ricin-induced apoptosis.

Subunit / interactions. Component of the BAG6/BAT3 complex, also named BAT3 complex, at least composed of BAG6, UBL4A and GET4/TRC35. Interacts with GET4; the interaction is direct and localizes BAG6 in the cytosol. Interacts with UBL4A; the interaction is direct and required for UBL4A protein stability. Interacts with AIFM1. Interacts with HSPA2. Interacts with CTCFL. Interacts with p300/EP300. Interacts (via ubiquitin-like domain) with RNF126; required for BAG6-dependent ubiquitination of proteins mislocalized to the cytosol. Interacts (via ubiquitin-like domain) with SGTA; SGTA competes with RNF126 by binding the same region of BAG6, thereby promoting deubiquitination of BAG6-target proteins and rescuing them from degradation. Interacts with ricin A chain. Interacts with VCP and AMFR; both form the VCP/p97-AMFR/gp78 complex. Interacts with SYVN1. Interacts with USP13; the interaction is direct and may mediate UBL4A deubiquitination. Interacts with ZFAND2B. Interacts with KPNA2. Interacts with UBQLN4. Interacts with MUL1/MAPL. (Microbial infection) Interacts with L.pneumophila Lpg2160 and LegU1 proteins.

Subcellular location. Cytoplasm. Cytosol. Nucleus. Secreted. Extracellular exosome.

Tissue specificity. Expressed by immature dendritic cells (at protein level).

Post-translational modifications. Ricin can induce a cleavage by the caspase CASP3. The released C-terminal peptide induces apoptosis. (Microbial infection) In case of infection by L.pneumophila, ubiquitinated by the SCF(LegU1) complex.

Domain organisation. The ubiquitin-like domain mediates interaction with the E3 ubiquitin-protein ligase RNF126 which is responsible for the BAG6-dependent ubiquitination of client proteins. SGTA also binds this domain and competes with RNF126 to antagonize client protein ubiquitination and degradation. The ubiquitin-like domain also mediates the interaction with USP13.

Isoforms (5)

UniProt ID	Names	Canonical?
P46379-1	1	yes
P46379-2	2
P46379-3	3
P46379-4	4
P46379-5	5

RefSeq proteins (59): NP_001092004, NP_001186626, NP_001186627, NP_001374869, NP_001374871, NP_001374872, NP_001374873, NP_001374875, NP_001374878, NP_001374880, NP_001374883, NP_001374884, NP_001374885, NP_001374887, NP_001374890, NP_001374892, NP_001374893, NP_001374894, NP_001374911, NP_001374912, NP_001374913, NP_001374914, NP_001374915, NP_001374916, NP_001374917, NP_001374918, NP_001374919, NP_001374920, NP_001374921, NP_001374922, NP_001374923, NP_001374924, NP_001374925, NP_001374926, NP_001374927, NP_001374928, NP_001374929, NP_001374930, NP_001374931, NP_001374932, NP_001374933, NP_001374934, NP_001374935, NP_001374936, NP_001374937, NP_001374938, NP_001374939, NP_001374940, NP_001374941, NP_001374942, NP_001374943, NP_001374944, NP_001374945, NP_001374946, NP_001374947, NP_001374948, NP_001374949, NP_542433, NP_542434 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR019954	Ubiquitin_CS	Conserved_site
IPR021925	BAG6	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR048926	Bag6_BAGS	Domain

Pfam: PF00240, PF12057, PF20960

UniProt features (91 total): compositionally biased region 13, sequence conflict 12, region of interest 11, modified residue 11, mutagenesis site 10, helix 10, strand 7, splice variant 6, repeat 4, sequence variant 2, chain 1, domain 1, short sequence motif 1, site 1, turn 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4EEW	X-RAY DIFFRACTION	1.3
4DWF	X-RAY DIFFRACTION	1.8
6AU8	X-RAY DIFFRACTION	1.8
4X86	X-RAY DIFFRACTION	1.85
4WWR	X-RAY DIFFRACTION	2
7RU9	ELECTRON MICROSCOPY	3.3
7RUA	ELECTRON MICROSCOPY	3.4
7RUC	ELECTRON MICROSCOPY	3.6
1WX9	SOLUTION NMR
2N9P	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46379-F1	58.52	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1001–1002 (cleavage; by casp3)

Post-translational modifications (11): 1, 96, 113, 117, 350, 964, 973, 1053, 1081, 1117, 832

Mutagenesis-validated functional residues (10):

Position	Phenotype
1001	abolishes cleavage by the caspase casp3.
1010	decreases interaction with get4. localizes in the nucleus and cytoplasm. decreases interaction with get4, localizes in t
1018	decreases interaction with get4. localizes in the nucleus. decreases interaction with get4, localizes in the nucleus and
1030–1031	no effect on interaction with get4 and kpna2.
1042	decreases interaction with get4. localizes in the nucleus. decreases interaction with get4, localizes in the nucleus and
1049–1050	no effect on interaction with get4. inhibits interaction with kpna2.
1067	no effect on interaction with ubl4a. no effect on interaction with ubl4a; when associated with a-1078. abolishes on inte
1078	no effect on interaction with ubl4a. no effect on interaction with ubl4a; when associated with r-1067 or r-1085.
1085	no effect on interaction with ubl4a. no effect on interaction with ubl4a; when associated with r-1078. abolishes on inte
1088	no effect on interaction with ubl4a.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane
R-HSA-9609507	Protein localization

MSigDB gene sets: 262 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, PAX4_01, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MORF_UBE2I, MORF_HDAC1, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, DARWICHE_SKIN_TUMOR_PROMOTER_DN

GO Biological Process (31): kidney development (GO:0001822), immune response-activating cell surface receptor signaling pathway (GO:0002429), chromatin organization (GO:0006325), ubiquitin-dependent protein catabolic process (GO:0006511), post-translational protein targeting to endoplasmic reticulum membrane (GO:0006620), apoptotic process (GO:0006915), synaptonemal complex assembly (GO:0007130), spermatogenesis (GO:0007283), brain development (GO:0007420), proteasomal protein catabolic process (GO:0010498), internal peptidyl-lysine acetylation (GO:0018393), natural killer cell activation (GO:0030101), cell differentiation (GO:0030154), lung development (GO:0030324), regulation of protein stability (GO:0031647), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), ERAD pathway (GO:0036503), obsolete maintenance of unfolded protein (GO:0036506), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of proteolysis (GO:0045861), regulation of embryonic development (GO:0045995), protein stabilization (GO:0050821), NK T cell activation (GO:0051132), endoplasmic reticulum stress-induced pre-emptive quality control (GO:0061857), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), tail-anchored membrane protein insertion into ER membrane (GO:0071816), positive regulation of ERAD pathway (GO:1904294), immune system process (GO:0002376), regulation of apoptotic process (GO:0042981)

GO Molecular Function (14): signaling receptor binding (GO:0005102), Hsp70 protein binding (GO:0030544), polyubiquitin modification-dependent protein binding (GO:0031593), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), ribosome binding (GO:0043022), receptor ligand activity (GO:0048018), misfolded protein binding (GO:0051787), molecular adaptor activity (GO:0060090), proteasome binding (GO:0070628), protein carrier activity (GO:0140597), molecular function activator activity (GO:0140677), ubiquitin-specific protease binding (GO:1990381), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), extracellular exosome (GO:0070062), BAT3 complex (GO:0071818), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
animal organ development	3
protein binding	3
binding	2
renal system development	1
immune response-activating signaling pathway	1
immune response-regulating cell surface receptor signaling pathway	1
cellular component organization	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein targeting to membrane	1
protein targeting to ER	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
homologous chromosome pairing at meiosis	1
cellular component assembly	1
chromosome organization involved in meiotic cell cycle	1
synaptonemal complex organization	1
developmental process involved in reproduction	1
male gamete generation	1
central nervous system development	1
head development	1
protein catabolic process	1
internal protein amino acid acetylation	1
peptidyl-lysine acetylation	1
lymphocyte activation	1
cellular developmental process	1
respiratory tube development	1
respiratory system development	1
regulation of biological quality	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1

Protein interactions and networks

STRING

1318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BAG6	GET4	Q7L5D6	990
BAG6	UBL4A	P11441	986
BAG6	NCR3	O14931	982
BAG6	HAVCR2	Q8TDQ0	914
BAG6	SGTA	O43765	890
BAG6	GET3	O43681	808
BAG6	FYN	P06241	747
BAG6	LCK	P06239	744
BAG6	PRRC2A	P48634	710
BAG6	RNF126	Q9BV68	683
BAG6	GOLPH3	Q9H4A6	666
BAG6	MRPL58	Q14197	596
BAG6	NCR3LG1	Q68D85	571
BAG6	KLRK1	P26718	564
BAG6	ATP5PF	P18859	542

IntAct

299 interactions, top by confidence:

A	B	Type	Score
ATG13	ULK1	psi-mi:“MI:2364”(proximity)	0.940
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
BAG6	RNF126	psi-mi:“MI:0915”(physical association)	0.890
RNF126	BAG6	psi-mi:“MI:0915”(physical association)	0.890
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
BAG6	SGTA	psi-mi:“MI:0915”(physical association)	0.800
SGTA	BAG6	psi-mi:“MI:0915”(physical association)	0.800
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
PKMYT1	CCNB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
BAG6	EFEMP1	psi-mi:“MI:0915”(physical association)	0.670
BAG6	KLHL12	psi-mi:“MI:0915”(physical association)	0.670
EFEMP1	BAG6	psi-mi:“MI:0915”(physical association)	0.670
KLHL12	BAG6	psi-mi:“MI:0915”(physical association)	0.670
GET3	GET1	psi-mi:“MI:0914”(association)	0.640
NCR3	BAG6	psi-mi:“MI:0915”(physical association)	0.610
NCR3	BAG6	psi-mi:“MI:0407”(direct interaction)	0.610

BioGRID (709): SED5 (Co-localization), BAG6 (Two-hybrid), BAG6 (Two-hybrid), BAG6 (Two-hybrid), RNF126 (Two-hybrid), KLHL12 (Two-hybrid), FAM9B (Two-hybrid), BAG6 (Co-crystal Structure), BAG6 (Reconstituted Complex), SGTA (Reconstituted Complex), BAG6 (Affinity Capture-MS), BAG6 (Affinity Capture-Western), BAG6 (Reconstituted Complex), USP13 (Reconstituted Complex), BAG6 (Affinity Capture-Western)

ESM2 similar proteins: A0A482PJY4, A2AH22, A3KPW9, A4IH17, A5D9M6, A7X5R6, A8Y4B2, B3P4M4, B4HJA7, B4KCG1, B4N8G7, B4PVI7, B4QVV3, E7FAG6, O22197, O74757, P0CH30, P32628, P32828, P38428, P46379, Q09463, Q0II22, Q20798, Q3KPV4, Q68FU0, Q6DIP3, Q6FS98, Q6IRP0, Q6MG49, Q6P135, Q6PA26, Q6PC78, Q7T0Q3, Q8LPN7, Q91W67, Q91YL2, Q94AK4, Q96S82, Q9BV68

Diamond homologs: A3KPW9, A4IH17, A5D9M6, A7X5R6, C4YP88, D5LXJ0, P05759, P0C016, P0C224, P0C8R3, P0CG47, P0CG48, P0CG49, P0CG50, P0CG51, P0CG53, P0CG54, P0CG55, P0CG60, P0CG61, P0CG62, P0CG63, P0CG64, P0CG65, P0CG66, P0CG67, P0CG68, P0CG69, P0CG70, P0CG71, P0CG72, P0CG73, P0CG74, P0CG75, P0CG76, P0CG77, P0CG78, P0CG79, P0CG80, P0CG81

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
BAG6	“down-regulates quantity by destabilization”	PCK1	acetylation
SGTA	“up-regulates activity”	BAG6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 177 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	5	22.0×	3e-04
Defective CFTR causes cystic fibrosis	8	16.3×	1e-05
AUF1 (hnRNP D0) binds and destabilizes mRNA	7	16.1×	4e-05
The role of GTSE1 in G2/M progression after G2 checkpoint	10	14.9×	9e-07
Ubiquitin-dependent degradation of Cyclin D	6	14.8×	3e-04
Dengue Virus Genome Translation and Replication	5	14.7×	1e-03
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	8	14.3×	2e-05
SCF(Skp2)-mediated degradation of p27/p21	7	13.5×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
tail-anchored membrane protein insertion into ER membrane	5	34.4×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

158 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	9
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3139 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31639227:C:CC	acceptor_gain	1.0000
6:31639476:C:A	donor_gain	1.0000
6:31639516:T:A	donor_gain	1.0000
6:31640198:C:A	donor_loss	1.0000
6:31640221:CCA:C	donor_gain	1.0000
6:31640302:CATTC:C	acceptor_gain	1.0000
6:31640303:ATTC:A	acceptor_gain	1.0000
6:31640304:TTC:T	acceptor_gain	1.0000
6:31640305:TC:T	acceptor_gain	1.0000
6:31640306:CC:C	acceptor_gain	1.0000
6:31640307:C:CC	acceptor_gain	1.0000
6:31640308:T:A	acceptor_loss	1.0000
6:31640383:A:AC	donor_gain	1.0000
6:31640384:C:CG	donor_gain	1.0000
6:31640419:G:C	donor_gain	1.0000
6:31640533:G:C	acceptor_gain	1.0000
6:31640537:CAGA:C	acceptor_gain	1.0000
6:31640538:A:T	acceptor_gain	1.0000
6:31640540:A:AC	acceptor_gain	1.0000
6:31640540:A:C	acceptor_gain	1.0000
6:31640544:C:CT	acceptor_gain	1.0000
6:31640545:G:T	acceptor_gain	1.0000
6:31640705:C:CC	acceptor_gain	1.0000
6:31640707:G:C	acceptor_gain	1.0000
6:31640707:G:GC	acceptor_gain	1.0000
6:31640788:TTA:T	donor_loss	1.0000
6:31640789:TACCT:T	donor_loss	1.0000
6:31640790:A:C	donor_loss	1.0000
6:31640791:C:CA	donor_loss	1.0000
6:31640822:T:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000107232 (6:31653962 T>G), RS1000475386 (6:31640406 A>G), RS1000784201 (6:31640085 C>A,G,T), RS1000888823 (6:31643243 C>T), RS1000903830 (6:31646469 C>T), RS1001164223 (6:31650362 G>A,T), RS1001164231 (6:31652319 A>C), RS1001492417 (6:31652661 C>A), RS1001606738 (6:31648891 C>G), RS1001678462 (6:31644268 T>C), RS1002060965 (6:31642620 G>A), RS1002273482 (6:31649721 C>G,T), RS1002411823 (6:31642252 G>A), RS1002778502 (6:31654294 T>C), RS1002931043 (6:31638743 G>A,T)

Disease associations

OMIM: gene MIM:142590 | disease phenotypes: MIM:300049

GenCC curated gene-disease

Mondo (2): isolated unilateral hemispheric cerebellar hypoplasia (MONDO:0017112), periventricular nodular heterotopia (MONDO:0020341)

Orphanet (2): Isolated unilateral hemispheric cerebellar hypoplasia (Orphanet:269218), Periventricular nodular heterotopia (Orphanet:98892)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

47 associations (top):

Study	Trait	p-value
GCST000257_1	Lung cancer	5.000000e-10
GCST000459_5	Lung cancer	4.000000e-10
GCST000506_1	Lung adenocarcinoma	5.000000e-12
GCST001851_7	Schizophrenia	4.000000e-06
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_224	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_281	Autism spectrum disorder or schizophrenia	5.000000e-09
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST004746_9	Small cell lung carcinoma	8.000000e-06
GCST005541_17	Sarcoidosis (Lofgren’s syndrome vs non-Lofgren’s syndrome)	1.000000e-30
GCST007327_22	Smoking status (ever vs never smokers)	3.000000e-08
GCST007931_34	Medication use (HMG CoA reductase inhibitors)	4.000000e-14
GCST008163_554	Height	4.000000e-08
GCST008916_111	Asthma	2.000000e-14
GCST008916_114	Asthma	1.000000e-09
GCST008916_30	Asthma	1.000000e-09
GCST008917_2	Asthma (childhood onset)	4.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D054091	Periventricular Nodular Heterotopia	C10.500.507.450.750; C16.131.666.507.450.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066898 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs750332	Toxicity	3	carbamazepine

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs750332	BAG6, PRRC2A	3	3.00	1	carbamazepine

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.49	Kd	3.268	nM	CHEMBL5653589
8.49	ED50	3.268	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147938: Binding affinity to human BAG6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0033	uM

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects methylation	2
Lead	affects splicing, decreases expression	2
Smoke	increases expression, decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
salinomycin	decreases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bisphenol S	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650980	Binding	Binding affinity to human BAG6 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SE64	HAP1 BAG6 (-) 1	Cancer cell line	Male
CVCL_SE65	HAP1 BAG6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05696912	Not specified	UNKNOWN	Functional Tests to Resolve Unsolved Rare Diseases. Rares.