Extracellular heat shock protein 90 plays a role in translocating chaperoned antigen from endosome to proteasome for generating antigenic peptide to be cross-presented by dendritic cells.

Extracellular heat shock protein can deliver associated antigens into the MHC class I presentation pathway of antigen-presenting cells, a process called cross-presentation, thus inducing antigen-specific CD8(+) T-cell responses; however, the precise mechanism for intracellular antigen translocation and the processing pathway has not been fully elucidated. Here we demonstrate that cross-presentation of extracellular Hsp90-ovalbumin (OVA) protein complexes to specific CD8(+) T cells involves both classical proteasome-transporter-associated antigen processing (TAP)-dependent and TAP-independent-endosomal pathways. Using confocal microscopy, we found that the internalized extracellular Hsp90 and OVA co-localized with cytosolic proteasomes.

Targeting to static endosome is required for efficient cross-presentation of endoplasmic reticulum-resident oxygen-regulated protein 150-peptide complexes.

Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit intriguing, efficient CTL responses by cross-presentation via an as yet entirely unknown mechanism. Oxygen-regulated protein 150 (ORP150), also known as grp170, is an endoplasmic reticulum-resident HSP and is up-regulated by hypoxia. It has been demonstrated that ORP150 binds tumor-associated Ag peptides within cancer cells.

Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway.

It is well-established that heat shock proteins (HSPs)-peptides complexes elicit antitumor responses in prophylactic and therapeutic immunization protocols. HSPs such as gp96 and Hsp70 have been demonstrated to undergo receptor-mediated uptake by APCs with subsequent representation of the HSP-associated peptides to MHC class I molecules on APCs, facilitating efficient cross-presentation. On the contrary, despite its abundant expression among HSPs in the cytosol, the role of Hsp90 for the cross-presentation remains unknown.