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.

The melting pot of the MHC II peptidome

“…Chaperone-mediated autophagy relies on hsc-70 recognition of selected cargo proteins (KFERQ-like motives) which are delivered to lysosomes through the LAMP-2A translocation complex [56]. Interestingly all forms of autophagy rely on the hsc-70 chaperone to transport cytosolic peptides, misfolded polypeptides, or ubiquitinated proteins into MHC II-containing organelles [43,57]. In DC a decrease in endosomal transport of cytosolic self-antigens has been observed upon knock down of macroautophagy and ESCRT-mediated microautophagy [55], in thymic epithelial cells macroautophagy has been shown to shape the T cell repertoire [58], and in a B cell line knock down of chaperone-mediated autophagy decreased MHC II presentation of a cytosolic protein [59].…”

The HSV-1 immediate early protein ICP22 is a J-like protein required for Hsc70 reorganization during lytic infection

“…We are also intrigued by recent reports suggesting that the protein homeostatic machinery and Hsc70 in particular have been implicated in antiviral defense mechanisms such as aggresome formation, proteolytic degradation of viral proteins and autophagy (16,17). In addition to the management of nascent proteins and regulation of gene expression, the ability of ICP22 to relocalize Hsc70 into VICE domains in the nucleus may serve to prevent Hsc70 from carrying out antiviral activities elsewhere in the cell.…”

“…Hsc70 but not Hsp70 is required for chaperone-mediated autophagy (CMA) (12,13) and clathrin-mediated endocytosis (CME) (14,15). Interestingly, CMA has been implicated in MHC class II presentation of viral antigens (16,17) and clearance of viral pathogens (18), thus implicating Hsc70 in antiviral mechanisms. It is possible that recruitment of Hsc70 into VICE domains during HSV-1 infection may have evolved in part to counteract these antiviral mechanisms.…”

Autophagie, auto-immunité et maladies auto-immunes

“…C'est dans ce compartiment, une structure lamellaire observable par microscopie électronique, que se déroule l'essentiel du chargement des molécules de classe II. Les Ag ainsi capturés et apprêtés sont ensuite présentés à la surface des 5 La macroautophagie ( Figure 1B) [32][33][34]. On l'aura compris, l'état de maturation des autolysosomes ainsi que la densité de lysosomes « CMA-compétents » seront déterminants dans ce mécanisme intracellulaire.…”