BAG6

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.

BCL2-associated athanogene 6

ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins (PubMed:21636303).
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 (PubMed:20516149, PubMed:21636303, PubMed:21743475, PubMed:28104892).
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 (PubMed:20516149, PubMed:20676083, PubMed:28104892, PubMed:25535373).
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 (PubMed:24981174, PubMed:28104892, PubMed:27193484).
SGTA which prevents the recruitment of RNF126 to BAG6 may negatively regulate the ubiquitination and the proteasomal degradation of client proteins (PubMed:23129660, PubMed:25179605, PubMed:27193484).
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 (PubMed:21743475).
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 (PubMed:21636303).
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 (By similarity).
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 (PubMed:26565908).
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 (By similarity).
Also positively regulates apoptosis by interacting with and stabilizing the proapoptotic factor AIFM1 (By similarity).
By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).
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 (PubMed:17403783).
When nuclear, may also act as a component of some chromatin regulator complex that regulates histone 3 'Lys-4' dimethylation (H3K4me2) (PubMed:18765639).
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.

Apoptotic process Source: UniProtKB
Brain development Source: UniProtKB
Cell differentiation Source: UniProtKB-KW
Chromatin organization Source: UniProtKB-KW
Endoplasmic reticulum stress-induced pre-emptive quality control Source: UniProtKB
ER-associated misfolded protein catabolic process Source: UniProtKB
Immune response-activating cell surface receptor signaling pathway Source: UniProtKB
Internal peptidyl-lysine acetylation Source: UniProtKB
Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: UniProtKB
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: UniProtKB
Kidney development Source: UniProtKB
Lung development Source: UniProtKB
Maintenance of unfolded protein involved in ERAD pathway Source: ParkinsonsUK-UCL
Natural killer cell activation Source: UniProtKB
Negative regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
Negative regulation of proteolysis Source: UniProtKB
Positive regulation of ERAD pathway Source: ParkinsonsUK-UCL
Proteasomal protein catabolic process Source: UniProtKB
Protein localization to cytosolic proteasome complex involved in ERAD pathway Source: ParkinsonsUK-UCL
Protein stabilization Source: UniProtKB
Regulation of embryonic development Source: UniProtKB
Spermatogenesis Source: UniProtKB
Synaptonemal complex assembly Source: UniProtKB
Tail-anchored membrane protein insertion into ER membrane Source: UniProtKB
Ubiquitin-dependent ERAD pathway Source: UniProtKB
Ubiquitin-dependent protein catabolic process Source: UniProtKB

Extracellular exosome; Cytosol; Nucleus. Normally localized in cytosol and nucleus, it can also be released extracellularly, in exosomes, by tumor and myeloid dendritic cells (PubMed:18055229, PubMed:18852879). Cytoplasmic retention is due to interaction with GET4 (PubMed:29042515).

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.