Figure 2.

ER stress and its possible effects on antigen presentation. (a) Intracellular self and pathogen proteins are degraded by the proteasome to form peptides that are transported to the ER and coupled to the major histocompatibility complex (MHC) Class I molecules, before being transported to the cell surface where they are recognised by immune cells, for example, dendritic cells (DC). Professional APCs can also present antigens on MHC Class II. (b) During ER‐associated protein degradation (ERAD), misfolded proteins accumulated within the ER are translocated to the proteasome for degradation into peptides. Misfolding can thereby result in greater presentation on MHC Class I at the cell surface resulting in increased likelihood of activation of autoreactive T cells. (c) Misfolded proteins unable to be cleared by ERAD activate PERK and IRE1 and their downstream factors eIF2α and JNK, respectively, which can activate autophagy; a process by which misfolded protein aggregates from the ER are engulfed and degraded by lysosomal proteins. Autophagy in APCs can result in reduced protein processing by the proteasome from the ER, hence reduced peptide loading and reduced MHC Class I presentation at the cell surface, although there is some evidence for derivation of Class I peptides from autophagolysosomes. Autophagy could also result in increased presentation of self‐proteins on MHC Class II. (d) During the UPR, GRP78 dissociates from PERK, allowing the phosphorylation of eIF2α, which can inhibit protein translation, potentially resulting in reduced synthesis of MHC molecules and an overall reduction in protein degradation and peptide loading onto MHC, and therefore reduced antigen presentation. A full colour version of this figure is available at the Immunology and Cell Biology journal online.