Alternative pathways for MHC class I presentation: a new function for autophagy

Abstract

The classical view that endogenous antigens are processed by the proteasome and loaded on MHC class I molecules in the endoplasmic reticulum, while exogenous antigens taken up by endocytosis or phagocytosis are degraded and loaded on MHC class II in lysosome-derived organelles, has evolved along with the improvement of our understanding of the cell biology of antigen-presenting cells. In recent years, evidence for alternative presentation pathways has emerged. Exogenous antigens can be processed by the proteasome and loaded on MHC class I through a pathway called cross-presentation. Moreover, endogenous antigens can be targeted to lytic organelles for presentation on MHC class II through autophagy, a highly conserved cellular process of self-eating. Recent evidence indicates that the vacuolar degradation of endogenous antigens is also beneficial for presentation on MHC class I molecules. This review focuses on how various forms of autophagy participate to presentation of these antigens on MHC class I.

Fig. 1

Mechanisms of autophagy in eukaryotic cells. In chaperone-mediated autophagy (CMA), cytoplasmic proteins containing a specific signaling motif (red) are recognized by hsc70 that subsequently associates with LAMP-2a (green) on the lysosomal membrane, allowing the translocation of the target protein into the lysosomal lumen (1). Alternatively, small portions of the cytoplasm can be taken up into lysosomes by invagination of the lysosomal membrane (microautophagy, 2). Intracellular pathogens (red hexagons), organelles and cytosolic protein aggregates (orange circles) can also be taken up by macroautophagy/xenophagy (3). A cup-shaped isolation membrane that can be in close association with the rough endoplasmic reticulum forms around the cargo. Membrane expansion and formation of the closed autophagosome requires two ubiquitin-like protein conjugation systems (blue circles: LC3, yellow and green squares: atg5/atg12). The cup closes into a vesicle bordered by two membrane layers that can subsequently fuse with lysosomes where its content and membrane components are degraded. Another autophagy pathway recently described in HSV1-infected macrophages uses the inner and outer leaflets of the nuclear envelope as a source of autophagosomal membrane (4). Protrusions originating from the nuclear membrane form a cup around virus particles or cytoplasmic components and finally close in on themselves, bud off the nucleus and fuse with lysosomes. Like the classical double-membrane autophagosomes, the 4-membrane bound vesicles generated by this process contain the autophagy marker LC3

Fig. 2

Pathways of antigen presentation on MHC class I. In the classical pathway (left), endogenous antigens in the cytosol are cleaved by the proteasome (1). Resulting peptides are transported into the ER via TAP, and loaded onto MHC class I molecules that are transported to the cell surface via the secretory pathway. In an alternative vacuolar pathway (right), antigens could be degraded by proteases in a lytic vacuole either after chaperone-mediated autophagy (CMA, 2) or macroautophagy/xenophagy (3). Peptides generated in the lytic vacuole might then return to the cytosol by a transporter like sec61. These antigens could then enter the classical pathway after a potential further trimming by the proteasome (4). Alternatively, peptides could stay in the endovacuolar pathway and be loaded onto MHC class I molecules (5). Newly loaded MHC class I complexes could be transported directly back to the cell surface by recycling vesicles. This vacuolar pathway of antigen presentation might be of particular importance in TAP-deficient cells or cells infected with viruses that can interfere with TAP or MHC class I processing and transport. Peptides generated by the proteasome can also be transported to neighboring cells via gap junctions. Last but not least, peptide cleavage can also occur by the protease furin in the Golgi