| Summary: | The human adenovirus has developed several methods to evade the immune system. One
mechanism by which it accomplishes this involves the endoplasmic reticulum (ER) retained
adenovirus E3/19K protein. This protein interferes with antigen presentation by binding and
retaining Major Histocompatibility Complex Class I (MHC C1 I) proteins in the ER.
E3/19K binds all human and all but one mouse MHC C1 I molecules tested to date. Differences
in mouse MHC C1 I sequences were exploited to determine the structures involved in binding.
Human 293 cells transfected with the mouse H-2 alleles K[sup d], K[sup b], K[sup k], D[sup d], D[sup b], L[sup d] were infected
with adenovirus 2. It was found that MHC C1 I alleles could be grouped into three categories.
The H-2 allelic proteins K[sup d] and K[sup b] were found to be binders; K[sup k] and D[sup d] non binders and D[sup b]
and L[sup d] slow binders.
Examination of a cell line transfected with the slow-binding H-2D[sup b] protein revealed that D[sup b] is
expressed at a reduced level at the cell surface. To determine the cause of this, cells were
subjected to conditions previously used to restore defective cell surface expression of MHC C1
I including culture at reduced temperature, addition of excess β₂m and exposure to gamma
interferon. All these methods were unsuccessful in increasing cell surface expression of Db.
Rather than being due to a missing co-factor or unstable conformation, the accumulation of the
allelic proteins in the ER in this transfectant was due to an undetermined mechanism.
Because E3/19K binding quickly stabilised a mature MHC C1 I conformation in the presence of
tunicamycin it was suggested that it bound MHC C1 I like a chaperone. It was found that
E3/19K binding to MHC C1 I did not block the association of endogenous ER resident
chaperones calnexin and TAP. Peptide binding to the MHC C1 I-E3/19K complex could also
occur. These experiments showed that E3/19K did not associate with MHC C1 I through the
peptide binding groove and did not disrupt the interaction between the MHC C1 I and the
processing machinery found in the ER, namely calnexin and TAP, and therefore does not retain
MHC molecules by making them conformationally immature.
This study shows E3/19K works independently of chaperones. E3/19K may be a tool to trap
MHC C1 I - chaperone complexes at a specific point in their maturation. === Science, Faculty of === Zoology, Department of === Graduate
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