Biology Reference
In-Depth Information
the past, here we focus on recent findings regarding host molecules interacting with
US2, US11, and US3, 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 func-
tional 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 dur-
ing US11-mediated degradation (Hassink et al. 2006), and each requires differ-
ent 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 disloca-
tion 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 dis-
location 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)
