Pathogen evasion strategies for the major histocompatibility complex class I assembly pathway

Abstract

Major histocompatibility complex (MHC) class I molecules bind and present short antigenic peptides from endogenously or exogenously derived sources to CD8(+) cytotoxic T lymphocytes (CTL), with recognition of a foreign peptide normally targeting the cell for lysis. It is generally thought that the high level of MHC polymorphism, which is concentrated mostly within the peptide-binding groove, is driven by the 'evolutionary arms race' against pathogens. Many pathogens have developed novel and intriguing mechanisms for evading the continuous sampling of the intracellular and intercellular environments by MHC molecules, none more so than viruses. The characterization of immunoevasion mechanisms has improved our understanding of MHC biology. This review will highlight our current understanding of the MHC class I biosynthetic pathway and how it has been exploited by pathogens, especially viruses, to potentially evade CTL recognition.

Figure 1

Early stages of major histocompatibility complex (MHC) class I assembly; newly synthesized MHC class I heavy (H) chain is translocated through the Sec61 channel. It remains undetermined whether newly synthesized or misfolding H chain associates with immunoglobulin-binding protein (BiP; step 1). Calnexin (CNX) associates with newly synthesized H chains via a monoglucosylated sugar moiety (G). The relationship between BiP and calnexin-associated H chain remains undefined (step 2). Calnexin can recruit ERp57 (step 3) to aid in the folding of native protein. ERp57 can be found in direct association with MHC class I H chains (steps 4 and 5). MHC class I H chain association with β2-microglobulin (β2m) leads to calnexin displacement and can promote disulphide bond formation (step 6).

Figure 2

Inhibition of the early stages of assembly; US11 and US2 enhance the endoplasmic reticulum-associated degradation pathway of major histocompatibility complex (MHC) class I heavy (H) chains but through distinct pathways. US11 recruits a dislocation complex composed of Derlin1, VIMP and a p97 complex. The H chain is retrotranslocated into the cytosol and targeted for degradation by ubquitination (Ub) through the activity of E2 and E3 ligases such as SelL1. The H chain is deglycosylated by the N glyconase Pgn before proteolytic degradation. US2 appears to recruit a different set of proteins. Signal peptide peptidase is thought to work in concert with as yet defined protein(s) (?), which can lead to the enhanced proteasome mediated degradation of H chain.

Figure 3

The peptide loading complex; partially folded major histocompatibility complex (MHC) class I molecules in association with calreticulin are incorporated into the peptide loading complex (PLC). MHC class I heavy (H) chains interact with tapasin (TPN) which tethers them to the transporter associated with antigen processing (TAP) complex. TPN is directly conjugated to ERp57 via a disulphide bond. The ERp57–TPN conjugate, possibly in concert with protein disulphide isomerise (PDI) allow for the acquisition of optimal peptides that are transported in an ATP-dependent manner by the TAP complex.

Figure 4

Inhibition of the peptide loading complex (PLC); the adenovirus E19 protein and the human cytomegalovirus (HCMV) US3 protein can both retain major histocompatibility complex (MHC) class I molecules, thereby preventing their transit to the cell surface (step 1). Both E19 and US3 can interfere with tapasin (TPN) activity (step 2), with US3 also enhancing the degradation of protein disulphide isomerise (PDI) in an undefined manner (step 3). The PLC is further targeted by inhibition of the peptide supply. ICP47 can act as a peptide inhibitor (step 4), while US6 prevents ATP hydrolysis (step 5). The mK3 protein inhibits the PLC by interacting with the MHC class I heavy (H) chain, transporter associated with antigen processing (TAP) and TPN, which can recruit Derlin1, VIMP and the p97 complex to enhance the degradation of these PLC components (step 6). Expression of MK3 is determined by TAP/TPN interactions, therefore modulating inhibition according to the level of antigen processing.