HSPA8

This gene encodes a member of the heat shock protein 70 family, which contains both heat-inducible and constitutively expressed members. This protein belongs to the latter group, which are also referred to as heat-shock cognate proteins. It functions as a chaperone, and binds to nascent polypeptides to facilitate correct folding. It also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

heat shock protein family A (Hsp70) member 8

Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488).

This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792).

The co-chaperones have been shown to not only regulate different steps of the ATPase cycle of HSP70, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792).

The affinity of HSP70 for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. HSP70 goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The HSP70-associated co-chaperones are of three types: J-domain co-chaperones HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP-bound state thereby promoting substrate release), and the TPR domain chaperones such as HOPX and STUB1 (PubMed:24318877, PubMed:27474739, PubMed:24121476, PubMed:26865365).

Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792).

Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:10722728, PubMed:11276205).

Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1 (PubMed:23990462).

Interacts with VGF-derived peptide TLQP-21 (PubMed:28934328).

ATP metabolic process Source: BHF-UCL
Cellular response to starvation Source: ParkinsonsUK-UCL
Cellular response to steroid hormone stimulus Source: Reactome
Cellular response to unfolded protein Source: GO_Central
Chaperone cofactor-dependent protein refolding Source: GO_Central
Chaperone-mediated autophagy Source: ParkinsonsUK-UCL
Chaperone-mediated autophagy translocation complex disassembly Source: ParkinsonsUK-UCL
Late endosomal microautophagy Source: GO_Central
Membrane organization Source: Reactome
mRNA processing Source: UniProtKB-KW
Negative regulation of supramolecular fiber organization Source: BHF-UCL
Negative regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation by host of viral genome replication Source: Ensembl
Positive regulation of mRNA splicing, via spliceosome Source: Ensembl
Protein folding Source: UniProtKB
Protein refolding Source: UniProtKB
Protein targeting to lysosome involved in chaperone-mediated autophagy Source: ParkinsonsUK-UCL
Regulation of cell cycle Source: Ensembl
Regulation of postsynapse organization Source: Ensembl
Regulation of protein complex stability Source: ParkinsonsUK-UCL
Regulation of protein-containing complex assembly Source: ParkinsonsUK-UCL
Regulation of protein import Source: ParkinsonsUK-UCL
Regulation of protein stability Source: ParkinsonsUK-UCL
Response to unfolded protein Source: UniProtKB
RNA splicing Source: UniProtKB-KW
Slow axonal transport Source: GO_Central
Vesicle-mediated transport Source: GO_Central

Nucleolus; Cytoplasm; Cell membrane; Melanosome. Localized in cytoplasmic mRNP granules containing untranslated mRNAs. Translocates rapidly from the cytoplasm to the nuclei, and especially to the nucleoli, upon heat shock.

Acetylated.
ISGylated.
Trimethylation at Lys-561 reduces fibrillar SNCA binding.