CD91: a receptor for heat shock protein gp96

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Antigen-presenting cells (APCs) process exogenous peptides chaperoned by heat shock protein gp96 via the endogenous pathway.
• Efficient re-presentation of gp96-chaperoned peptides by APCs suggests a specific receptor interaction.
• Heat shock protein gp96 is involved in antigen processing and presentation, particularly following cellular stress.

Purpose of the Study:

• To identify the cell surface receptor responsible for the uptake of heat shock protein gp96 by APCs.
• To elucidate the mechanism by which gp96-chaperoned peptides are re-presented by APCs.
• To investigate the functional role of the identified receptor in antigen presentation and cell death detection.

Main Methods:

• Direct binding assays to confirm the interaction between CD91 and heat shock protein gp96.
• Functional assays using macrophages to assess the re-presentation of gp96-chaperoned peptides.
• Inhibition studies using alpha 2-macroglobulin and anti-CD91 antibodies to block gp96 binding and peptide re-presentation.

Main Results:

• The CD91 molecule (alpha 2-macroglobulin receptor/low density lipoprotein-related protein) was identified as a direct cell surface receptor for heat shock protein gp96.
• Binding of gp96 to CD91 is direct, not mediated by other known CD91 ligands.
• Inhibition of CD91 by alpha 2-macroglobulin or antibodies blocked the re-presentation of gp96-chaperoned peptides by macrophages.

Conclusions:

• CD91 is the primary receptor for heat shock protein gp96 on antigen-presenting cells, mediating efficient peptide re-presentation.
• The interaction between CD91 and gp96 is crucial for the endogenous pathway of antigen presentation.
• Given that gp96 is released during necrotic cell death, CD91 likely functions as a sensor for this specific cell death pathway.