ReviewCowpox virus employs a two-pronged strategy to outflank MHCI antigen presentation
Highlights
► CPXV012 and CPXV203 work synergistically to block peptides from finding MHCI and targeting complexes that nevertheless form. ► CPXV203 promiscuously binds MHCI using sequence-conserved determinants located under the peptide-binding platform. ► CPXV203 preferentially associates with fully assembled MHCI in the Golgi, where it couples it to KDEL receptor mediated ER-retrieval.
Introduction
A recurrent theme in viral immune evasion is the disruption of MHC class I (MHCI) antigen processing and presentation pathways that otherwise lead to elimination of infected cells by cytotoxic T cells. Viral proteins that sabotage virtually every step of the process have been identified, including those that block peptide generation and transport, undermine peptide loading complex (PLC) assembly, and redirect MHCI intracellular trafficking (Hansen and Bouvier, 2009). For example, herpesviruses have developed strategies to dislocate MHCI proteins from the ER for degradation in the cytosol as well as to internalize cell surface MHCI for degradation in the lysosome. The mechanistic study of these viral proteins has provided considerable insight into the physiologic pathways used in antigen presentation, and has, for example, led to a far better appreciation of the role played by ubiquitin conjugation in MHCI sorting and quality control.
In contrast to other large-DNA viruses, orthopoxviruses such as vaccinia, variola and ectromelia are not known to evade MHCI antigen presentation. However, work in the Früh and Yokoyama labs independently discovered that cowpox does in fact block MHCI surface expression in a process facilitated by two immune evasion proteins. CPXV012 is a short-lived type II transmembrane protein that co-immunoprecipitates with the PLC and blocks transporter associated with antigen processing (TAP)-mediated transport of peptides into the ER (Byun et al., 2009, Alzhanova et al., 2009). Interestingly, CPXV012 appears to be a truncated C-type lectin domain with sequence similarity to a number of activating and inhibitory NK receptors. CPXV203, on the other hand, is a soluble protein that sequesters MHCI proteins within the ER by a mechanism that is independent of the PLC (Byun et al., 2007). However, the ER retention of MHCI by CPXV203 is dependent upon its C-terminal KTEL sequence, a motif known to bind to the KDEL receptor (KDELR) whose cellular function is the retrieval of proteins from the Golgi to the ER. Of note, cowpox viruses with deletions of the CPXV012 and CPXV203 ORFs exhibit attenuated virulence in a manner dependent upon CD8+ T cell control (Byun et al., 2009), an observation that stands in stark contrast to similar manipulations of beta- and gamma-herpesviruses where it has been difficult to show an in vivo role for viral MHCI modulation during acute infection. More recent experiments indicate that MHCI targeting by cowpox affects virus-specific CD8+ effector responses but not T-cell priming (Gainey et al., 2012).
Section snippets
CPXV203 binds in a niche under the peptide-binding platform of MHCI
CPXV203 is capable of preventing the cell surface expression of a wide array of MHCI proteins, and we recently have shown that this feat is accomplished by direct binding to the luminal domains of MHCI (McCoy et al., 2012). Our work has also revealed that CPXV203 adopts a compact beta-sandwich structure surprisingly reminiscent of the vCCI and SECRET decoy receptors encoded by poxviruses, although the established determinants for chemokine binding are largely absent. CPXV203 binds underneath
References (9)
- et al.
Cowpox virus inhibits the transporter associated with antigen processing to evade T cell recognition
Cell Host & Microbe
(2009) - et al.
Two mechanistically distinct immune evasion proteins of cowpox virus combine to avoid antiviral CD8 T cells
Cell Host & Microbe
(2009) - et al.
Cowpox virus exploits the endoplasmic reticulum retention pathway to inhibit MHC class I transport to the cell surface
Cell Host & Microbe
(2007) - et al.
Viral MHC class I inhibition evades CD8+ T-cell effector responses in vivo but not CD8+ T-cell priming
Proceedings of the National Academy of Sciences
(2012)
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2019, Molecular ImmunologyCitation Excerpt :CPXV203 was found to target fully assembled MHC-I molecules and to retain them in the ER. A deletion of CPXV203 did not fully restore MHC-I surface expression, indicating that a second protein might be involved in the inhibition of this pathway (McCoy et al., 2013). Subsequently, CPXV012 was identified as the second CPXV protein that interferes with MHC-I-mediated antigen presentation (Alzhanova et al., 2009; Byun et al., 2009).
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