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Expression of Endoplasmic Reticulum Aminopeptidases in EBV-B Cell Lines from Healthy Donors and in Leukemia/Lymphoma, Carcinoma, and Melanoma Cell Lines¹

Doriana Fruci^2,*, Silvia Ferracuti^*, Maria Zaira Limongi^3,*, Veronica Cunsolo^3,*, Ezio Giorda^4,, Rocco Fraioli, Leonardo Sibilio, Oliver Carroll, Akira Hattori^¶, Peter M. van Endert and Patrizio Giacomini^,

^* Research Center Ospedale Bambino Gesù, Rome, Italy; Laboratory of Immunology and Melanoma Disease Management Team, Regina Elena Institute, Centro della Ricerca Sperinentale, Rome, Italy; Institut National de la Santé et Recherche Médicale, Unité 580, Necker Institute, Paris, France; and ^¶ Laboratory of Cellular Biochemistry, RIKEN, Institute of Physical and Chemical Research, Wako, Japan

Peptide trimming in the endoplasmic reticulum (ER), the final step required for the generation of most HLA class I-binding peptides, implicates the concerted action of two aminopeptidases, ERAP1 and ERAP2. Because defects in the expression of these peptidases could lead to aberrant surface HLA class I expression in tumor cells, we quantitatively assayed 14 EBV-B cell lines and 35 human tumor cell lines of various lineages for: 1) expression and enzymatic activities of ERAP1 and ERAP2; 2) ER peptide-trimming activity in microsomes; 3) expression of HLA class I H chains and TAP1; and 4) surface HLA class I expression. ERAP1 and ERAP2 expression was detectable in all of the EBV-B and tumor cell lines, but in the latter it was extremely variable, sometimes barely detectable, and not coordinated. The expression of the two aminopeptidases corresponded well to the respective enzymatic activities in most cell lines. A peptide-trimming assay in microsomes revealed additional enzymatic activities, presumably contributed by other unidentified aminopeptidases sharing substrate specificity with ERAP2. Interestingly, surface HLA class I expression showed significant correlation with ERAP1 activity, but not with the activity of either ERAP2 or other unidentified aminopeptidases. Transfection with ERAP1 or ERAP2 of two tumor cell lines selected for simultaneous low expression of the two aminopeptidases resulted in the expected, moderate increases of class I surface expression. Thus, low and/or imbalanced expression of ERAP1 and probably ERAP2 may cause improper Ag processing and favor tumor escape from the immune surveillance.

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