Biology Reference
In-Depth Information
MHC-I complexes are heterotrimers consisting of a 45-kDa type 1 transmembrane
glycoprotein heavy chain (HC), the 12-kDa light chain β2-microglobulin (β2m), and
a nine amino acid peptide. MHC-I-bound peptides are proteasomal breakdown prod-
ucts 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 US11 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
