A central role for HSC70 in regulating antigen trafficking and MHC class II presentation

Abstract

Cells rely on multiple intracellular trafficking pathways to capture antigens for proteolysis. The resulting peptides bind to MHC class II molecules to promote CD4(+) T cell recognition. Endocytosis enhances the capture of extracellular and cell surface bound antigens for processing and presentation, while autophagy pathways shunt cytoplasmic and nuclear antigens for presentation in the context of MHC class II molecules. Understanding how physiological changes and cellular stress alter antigen trafficking and the repertoire of peptides presented by class II molecules remains challenging, yet important in devising novel approaches to boost immune responses to pathogens and tumors. An abundant, constitutively expressed cytoplasmic chaperone, HSC70 plays a central role in modulating antigen transport within cells to control MHC class II presentation during nutrient stress. HSC70 may serve as a molecular switch to modulate endocytic and autophagy pathways, impacting the source of antigens delivered for MHC class II presentation during cellular stress.

Keywords: Antigen presentation; Autophagy; Cell stress; HSC70; MHC class II molecules.

Figure 1. The role of HSC70 in MHC class II antigen trafficking and presentation

Exogenous Ags are internalized via clathrin-mediated endocytosis and delivered to the endosomal/lysosomal network. Endogenous Ags can be delivered by autophagy pathways such as macroautophagy (MA) and chaperone-mediated autophagy (CMA). Once delivered into the endosomal/lysosomal network, acidic proteases within these compartments process the Ag into small peptides. These peptides then bind MHC class II molecules. MHC class II:peptide complexes are shuttled to the surface to be displayed for recognition by CD4⁺ T cells. HSC70 is required for clathrin-mediated endocytosis, as the ATPase activity of HSC70 is required for coating and uncoating of vesicles. HSC70 is a key component of CMA, binding to client proteins and guiding them to the lysosomal membrane for interactions with LAMP2A. Furthermore, HSC70 in the lumen of the lysosome is required for translocation of these peptides. While association of HSC70 with autophagsome membranes has been detected, the function of this has not been established though it may be related to selective-autophagy. During selective-autophagy, HSC70 and its co-chaperone BAG3 guide client proteins to p62 and LC3, leading to their degradation via MA.