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Volume 271, Number 29, Issue of July 19, 1996 pp. 17275-17280
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Proteasome Subunits X and Y Alter Peptidase Activities in Opposite Ways to the Interferon--induced Subunits LMP2 and LMP7

(Received for publication, November 21, 1995, and in revised form, March 12, 1996)

Maria Gaczynska , Alfred L. Goldberg , Keiji Tanaka ^§ , Klavs B. Hendil ^¶ and Kenneth L. Rock ^''

From the Departments of  Cell Biology and  Pathology, Harvard Medical School, Boston, Massachusetts 02115, the ^'' Dana-Farber Cancer Institute, Boston, Massachusetts 02115, the ^§ Institute for Enzyme Research, University of Tokushima, Tokushima 770, Japan, and the ^¶ August Krogh Institute, University of Copenhagen, Universitetsparken 13, DK 2100 Copenhagen 0, Denmark

Most antigenic peptides presented on major histocompatibility complex class I molecules are generated by proteasomes. Interferon-, which stimulates antigen presentation, induces new proteasome -subunits LMP2 and LMP7, which replace the homologous -subunits Y () and X (). As a result, the capacity of the proteasome to cleave model peptides increases after hydrophobic and basic residues and falls after acidic residues. To clarify the function of these subunits, we examined the effects of overexpressing subunits X () and Y (). Transfection of the Y gene into HeLa cells stimulated the proteasomal cleavage after acidic residues without altering other peptidase activities. This effect was proportional to the amount of the Y subunits and opposite to the effect of its homolog, LMP2. Y appears to promote cleavages after acidic residues. Furthermore, in mutants lacking the LMP genes (in contrast to wild-type cells), interferon- treatment increased the proteasome content of Y subunits and enhanced postacidic cleavages. Transfection with cDNA for the X subunit reduced hydrolysis after hydrophobic and basic residues, an effect opposite to transfection of LMP2 and LMP7. Surprisingly, transfection of X increased the amounts not only of X, but also of Y, while decreasing LMP2 content. Thus, the loss of the Y subunit upon interferon- treatment or LMP2 transfection accounts for the suppression of postacidic cleavages, and the loss of X contributes to the increased hydrolysis after hydrophobic and basic residues. These adaptations should favor the production of the kinds of peptides that are presented on major histocompatibility complex class I molecules.

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