Peptidase Activities of Proteasomes are Differentially Regulated by the Major Histocompatibility Complex-Encoded Genes for LMP2 and LMP7

Recent studies have implicated proteasomes in the generation of the antigenic peptides that are presented on major histocompatibility complex class I molecules to T lymphocytes. Interferon γ modifies the subunit composition of proteasomes and causes changes in their peptidase activities that should...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-09, Vol.91 (20), p.9213-9217
Main Authors: Gaczynska, Maria, Rock, Kenneth L., Spies, Thomas, Goldberg, Alfred L.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antigens
B-Lymphocytes
Biochemistry
Cell Line
Cell lines
Complementary DNA
Cysteine Endopeptidases - metabolism
Endopeptidases - metabolism
Gene expression regulation
Gene Expression Regulation, Enzymologic
Genes
HeLa Cells
Humans
Hydrolysis
Interferon
Interferon-gamma - pharmacology
Interferons
Kinetics
Major Histocompatibility Complex
Molecular Sequence Data
Molecules
Multienzyme Complexes - metabolism
Oligopeptides - metabolism
Proteasome Endopeptidase Complex
Protein Biosynthesis
Proteins
Proteins - genetics
Substrate Specificity
T-Lymphocytes - immunology
Transfection
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Summary:Recent studies have implicated proteasomes in the generation of the antigenic peptides that are presented on major histocompatibility complex class I molecules to T lymphocytes. Interferon γ modifies the subunit composition of proteasomes and causes changes in their peptidase activities that should favor the production of peptides with hydrophobic or basic carboxyl termini (i.e., the types found on major histocompatibility complex class I molecules). It has been proposed that these changes in peptidase activity are due to incorporation into proteasomes of the major histocompatibility complex-encoded subunits LMP2 and -7, which are induced by interferon γ. Here we show by gene transfection into lymphoblasts or HeLa cells that LMP7 increases the capacity (Vmax) of 20S and 26S proteasomes to cleave peptides after hydrophobic and basic residues without affecting hydrolysis after acidic residues. These changes depended on the amount of LMP7 subunits incorporated into proteasomes. Transfection of LMP2 reduced cleavage of peptides after acidic residues, increased hydrolysis after basic residues, and did not affect the hydrophobic activity. Since the activity of the total proteasome population changed after incorporation of only small amounts of LMP2 or -7, these subunits must cause major alterations in peptidase activity. Thus, their expression can account for the changes in proteasome activity induced by interferon γ, and these findings lend further support to the proposed roles of LMPs in altering the nature of the peptides generated for antigen presentation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.20.9213