Heat shock protein gp96 (HSP90B1) (gp96)

Heat shock protein gp96 (HSP90B1), also known as endoplasmin or GRP-94, is a molecular chaperone primarily located in the endoplasmic reticulum where it assists in protein folding and quality control (UniProt: P14625). In the context of the immune system, gp96 plays a critical role as a chaperoadjuvant by binding to intracellular peptides and, when released or secreted (often as a gp96-Ig fusion protein in therapeutic contexts), delivering these antigens to professional antigen-presenting cells (APCs) like dendritic cells. This delivery occurs via the CD91 receptor, leading to efficient cross-presentation of antigens on MHC class I molecules to activate CD8+ cytotoxic T lymphocytes (PMID: 27160011). Furthermore, gp96 acts as a danger-associated molecular pattern (DAMP) that signals through Toll-like receptors 2 and 4 (TLR2/4), promoting APC maturation and the secretion of pro-inflammatory cytokines (PMID: 23543761). This dual role makes the gp96-mediated pathway a significant target for cancer immunotherapies, such as the cell-based vaccine viagenpumatucel-L (HS-110), which aims to convert cold tumors into hot tumors by stimulating a robust, antigen-specific T-cell response.

Other names

EndoplasminGRP-94TRA1Heat shock protein 90 beta family member 1gp96-IgTumor rejection antigen 1

The gp96-Ig fusion protein acts as a chaperone-adjuvant that captures tumor antigens and delivers them to antigen-presenting cells (APCs) via the CD91 receptor for MHC class I cross-presentation, while simultaneously triggering TLR2 and TLR4 signaling pathways to promote APC maturation and pro-inflammatory cytokine release (PMID: 23543761).