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J. Exp. Med.,
Volume 187, Number 1, January 5, 1998 37-48
By
From the * Department of Microbiology and the Beirne Carter Center for Immunology Research; Formation of major histocompatibility complex class I-associated peptides from membrane
proteins has not been thoroughly investigated. We examined the processing of an HLA-A*0201-associated epitope, YMDGTMSQV, that is derived from the membrane protein tyrosinase by posttranslational conversion of the sequence YMNGTMSQV. Only YMDGTMSQV and not YMNGTMSQV was presented by HLA-A*0201 on cells expressing full-length
tyrosinase, although both peptides have similar affinities for HLA-A*0201 and are transported by TAP. In contrast, translation of YMNGTMSQV in the cytosol, as a minigene or a larger
fragment of tyrosinase, led to the presentation of the unconverted YMNGTMSQV. This was
not due to overexpression leading to saturation of the processing/conversion machinery, since
presentation of the converted peptide, YMDGTMSQV, was low or undetectable. Thus, presentation of unconverted peptide was associated with translation in the cytosol, suggesting that processing of the full-length tyrosinase occurs after translation in the endoplasmic reticulum.
Nevertheless, presentation of YMDGTMSQV in cells expressing full-length tyrosinase was
TAP (transporter associated with antigen processing) and proteasome dependent. After inhibition of proteasome activity, tyrosinase species could be detected in the cytosol. We propose
that processing of tyrosinase involves translation in the endoplasmic reticulum, export of full-length tyrosinase to the cytosol, and retransport of converted peptides by TAP for association
with HLA-A*0201.
the
Department of Chemistry; § the Department of Surgery; and the Department of Pathology, University
of Virginia, Charlottesville, Virginia 22904
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