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. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. 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. 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. Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70. 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. Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1. Interacts with VGF-derived peptide TLQP-21. ATP + H2O = ADP + H(+) + phosphate Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (By similarity). Interacts with PACRG (By similarity). Interacts with HSPH1/HSP105 (By similarity). Interacts with IRAK1BP1 and BAG1 (By similarity). Interacts with DNAJC7 (By similarity). Interacts with DNAJB12 (via J domain) (By similarity). Interacts with DNAJB14 (via J domain) (By similarity). Interacts (via C-terminus) with the E3 ligase STUB1 forming a 210 kDa complex of one STUB1 and two HSPA8 molecules (By similarity). Interacts with CITED1 (via N-terminus); the interaction suppresses the association of CITED1 to p300/CBP and Smad-mediated transcription transactivation (By similarity). Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8 (By similarity). Interacts with TRIM5 (By similarity). Part of a complex composed at least of ASCL2, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity (By similarity). Interacts with METTL21A (By similarity). Following LPS binding, may form a complex with CXCR4, GDF5 and HSP90AA1 (By similarity). Interacts with PRKN (By similarity). Interacts with FOXP3 (By similarity). Interacts with DNAJC9 (via J domain) (By similarity). Interacts with MLLT11 (By similarity). Interacts with RNF207 (By similarity). Interacts with DNAJC21 (By similarity). Interacts with DNAJB2 (By similarity). Interacts with TTC1 (via TPR repeats) (By similarity). Interacts with SGTA (via TPR repeats) (By similarity). Interacts with HSF1 (via transactivation domain) (By similarity). Interacts with HOPX, STUB1, HSP40, HSP901, BAG2 and BAG3 (By similarity). Interacts with HSPC138 (By similarity). Interacts with ZMYND10 (By similarity). Interacts with VGF-derived peptide TLQP-21 (By similarity). Interacts with BCL2L1, GIMAP5 and MCL1; the interaction with BCL2L1 or MCL1 is impaired in the absence of GIMAP5 (By similarity). Interacts with NLPR12 (By similarity). Interacts with TTC4 (By similarity). Interacts with TOMM70; the interaction is required for preprotein mitochondrial import (By similarity). May interact with DNJC9; the interaction seems to be histone-dependent (By similarity). Localized in cytoplasmic mRNP granules containing untranslated mRNAs. Translocates rapidly from the cytoplasm to the nuclei, and especially to the nucleoli, upon heat shock (By similarity). Constitutively synthesized. The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. The C-terminal substrate-binding domain (SBD) (also known as peptide-binding domain) binds to the client/substrate proteins. The two domains are allosterically coupled so that, when ATP is bound to the NBD, the SBD binds relatively weakly to clients. When ADP is bound in the NBD, a conformational change enhances the affinity of the SBD for client proteins. Acetylated. ISGylated. Trimethylation at Lys-561 reduces fibrillar SNCA binding. Belongs to the heat shock protein 70 family.