Heat shock 70kDa protein 8 (HSPA8)

Heat shock 70kDa protein 8 (HSPA8), also known as HSC70, is a constitutively expressed member of the Hsp70 family that acts as a primary molecular chaperone in the cytoplasm and nucleus (UniProt: P11142). Unlike stress-induced heat shock proteins, HSPA8 is essential for cellular homeostasis, facilitating the folding of newly synthesized proteins and the refolding of misfolded ones. It plays a unique role in clathrin-mediated endocytosis by catalyzing the uncoating of clathrin from coated vesicles and is the central component of chaperone-mediated autophagy (CMA), directing specific proteins to the lysosome for degradation (PubMed: 25233119). In oncology, HSPA8 is frequently overexpressed, where it supports the stability of oncogenic drivers and protects cancer cells from proteotoxic stress (PubMed: 30107123). In autoimmune diseases like systemic lupus erythematosus, HSPA8 is involved in the processing and presentation of self-antigens, making it a target for the therapeutic peptide P140 (Lupuzor) (PubMed: 26109443). Therapeutic strategies targeting HSPA8 include small-molecule inhibitors of its ATPase activity and peptides that disrupt its interaction with co-chaperones or client proteins. However, because HSPA8 is ubiquitously expressed and vital for normal cell function, achieving a therapeutic window without significant off-target toxicity remains a major challenge in drug development.

Other names

Heat shock cognate 71 kDa proteinHSC70HSC71HSPA10LPS-associated protein 1LAP-1

Inhibition of the N-terminal ATPase domain to prevent ATP hydrolysis and subsequent substrate release, or modulation of chaperone-mediated autophagy (CMA) to alter lysosomal degradation of specific proteins (PubMed: 26109443, 30107123).