Inhibition of Antigen Presentation to CD8 T Lymphocytes

CD8+ T cells defend the host against viruses. They are able to kill infected cells upon recognizing virus-derived peptides displayed by MHC-I molecules at the cell surface.

MHC-I complexes are heterotrimers consisting of a 45-kDa type 1 transmembrane glycoprotein heavy chain (HC), the 12-kDa light chain p2-microglobulin (P2m), and a nine amino acid peptide. MHC-I-bound peptides are proteasomal breakdown products of both host and viral proteins. Proteolytic fragments are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen presentation (TAP) and loaded onto MHC-I with help from the chaperones tapasin, calreticulin, Erp57, and protein disulfide isomerase (PDI).

HCMV encodes at least four VIPRs targeting MHC-I: US2, US3, US6, and US11 (see Fig. 2); single transmembrane, immunoglobulin (Ig) domain superfamily glycoproteins (Gewurz et al. 2001). US8 and US10 interact with MHC-I but they do not inhibit antigen presentation (Furman et al. 2002a; Huber et al. 2002; Tirabassi and Ploegh 2002). US2 and US 11 retrotranslocate the HC from the ER to the cytosol for proteasomal degradation (reviewed in van der Wal et al. 2002). US3 binds MHC-I and causes ER retention (Ahn et al. 1996; Jones et al. 1996). US6 inhibits peptide transport and prevents ATP hydrolysis by TAP (Hewitt et al. 2001). Since the molecular function of these molecules has been reviewed extensively in

Fig. 2 CMVs encode multiple MHC-I modulators. An illustration of HCMV and MCMV mechanisms of MHC-I modulation. For details and references see the text. Both US2 and US11 cause the retrotranslocation of MHC-I heavy chains from the ER to the cytosol where they are degraded by the proteasome. Retrotranslocation is achieved by different mechanisms with US11 employing derlin-1, whereas US2 interacts with SPP. The transport of peptides via TAP is blocked by US6, inhibiting the ATP-hydrolysis step. US3 associates with the peptide loading complex and prevents optimal peptide loading in a tapasin (tpn)-dependent manner by causing the degradation of PDI. MCMV m04 forms a complex with MHC-I in the ER and at the cell surface, preventing T cell recognition. m06 redirects MHC-I to lysosomes for degradation. m152 retains MHC-I molecules in the ERGIC by an as yet unknown mechanism

Fig. 2 CMVs encode multiple MHC-I modulators. An illustration of HCMV and MCMV mechanisms of MHC-I modulation. For details and references see the text. Both US2 and US11 cause the retrotranslocation of MHC-I heavy chains from the ER to the cytosol where they are degraded by the proteasome. Retrotranslocation is achieved by different mechanisms with US11 employing derlin-1, whereas US2 interacts with SPP. The transport of peptides via TAP is blocked by US6, inhibiting the ATP-hydrolysis step. US3 associates with the peptide loading complex and prevents optimal peptide loading in a tapasin (tpn)-dependent manner by causing the degradation of PDI. MCMV m04 forms a complex with MHC-I in the ER and at the cell surface, preventing T cell recognition. m06 redirects MHC-I to lysosomes for degradation. m152 retains MHC-I molecules in the ERGIC by an as yet unknown mechanism the past, here we focus on recent findings regarding host molecules interacting with US2, US 11, and US 3, along with studies in MCMV characterizing the role of VIPRs in vivo.

US2 and US11 Cause Retrotranslocation of MHC-I Heavy Chains by Distinct Means

Both US2 and US11 interact with BiP (Hegde et al. 2006) and require a functional ubiquitin system (Hassink et al. 2006), but each has a distinct HLA allele specificity (van der Wal et al. 2002; Barel et al. 2006) and different requirements for function (Furman et al. 2002b). HC is ubiquitinated during US2, but not during US11-mediated degradation (Hassink et al. 2006), and each requires different cellular interactors for function (Lilley and Ploegh 2004; Hassink et al. 2006; Loureiro et al. 2006). HC dislocation by US11 is mediated by its transmembrane domain (Lilley et al. 2003), which contains a Gln residue essential for dislocation but not for the interaction with MHC-I (Lilley et al. 2003). Screening for cellular proteins interacting with US11 but not with the Gln-mutant identified Derlin-1, whose yeast homolog is required for the degradation of a subset of ER proteins (Lilley and Ploegh 2004). Independently, Derlin-1 was identified as a multiple transmembrane domain protein responsible for recruiting to the ER the cytosolic ATPase p97, a protein required for retrotranslocation (Ye et al. 2004). Both studies further proposed that Derlin-1 is a component of the retrotransloca-tion channel.

Interestingly, a dominant negative Derlin-1 failed to prevent dislocation by US2 (Lilley and Ploegh 2004). A screen for cellular proteins interacting with wild type but not dislocation-defective US2 implicated signal peptide peptidase (SPP) in HC dislocation by US2 but not US11 (Loureiro et al. 2006). While the cytosolic tail of US2 is required for SPP binding, it is not sufficient for dislocation since US2 containing the CD4 transmembrane domain was unable to cause dislocation. This indicates a necessary interaction between the US2 transmembrane domain and either SPP or some other protein (Loureiro et al. 2006). Thus, US2 and US11 might have evolved independently to achieve MHC-I destruction by different molecular means.

US3 Inhibits Optimal Peptide Loading

Recently two studies have further investigated the molecular mechanisms by which US3 retains MHC-I in the ER (Park et al. 2004, 2006). Both studies revealed that US3 prevented the optimization of peptide loading onto MHC-I heterodimers. Peptide loading is optimized by Tapasin, which forms a transient complex with empty MHC-I, and TAP and releases MHC-I peptide complexes (Schoenhals et al. 1999; Grandea and Van Kaer 2001; Purcell et al. 2001; Williams et al. 2002; Cresswell et al. 2005). The availability of MHC-I binding peptides regulates the duration of this transient complex resulting in fast (tapasin-independent) and slowly exiting (tapasin-dependent)

MHC-I alleles (Thammavongsa et al. 2006). US3 was shown to preferentially retain tapasin-dependent MHC-I alleles by inhibiting their acquisition of high-affinity peptides, whereas tapasin-independent alleles were not affected (Park et al. 2004). The same group recently identified a critical role of PDI in stabilizing the peptide-receptive site of MHC-I by regulating the oxidation of the a2 disulfide bond in the peptide-binding groove (Park et al. 2006). Interestingly, PDI protein levels were decreased in the presence of US3 and a complex between US3 and PDI is stabilized by proteasome inhibitors. By degrading PDI, US3 inhibits the binding of high-affinity peptides to tapasin-dependent alleles of MHC-I. Since PDI and tapasin are part of the peptide loading complex and can be co-immunoprecipitated, it is likely that previously observed interactions between US3 and MHC-I or tapasin are the result of US3 entering the peptide loading complex (Park et al. 2006).

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