γ-Interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes

Maria Gaczynska, Kenneth L. Rock, Alfred L. Goldberg

Research output: Contribution to journalArticle

475 Scopus citations

Abstract

THE presentation of intracellular proteins to the immune system requires their degradation to small peptides1,2 that then become associated with major histocompatibility complex (MHC) class I molecules3,4. The generation of these peptides may involve the 20S or 26S proteasome particles, which contain multiple proteolytic activitiesincluding distinct sites that preferentially cleave small peptides on the carboxyl side of hydrophobic, basic or acidic residues6,13,14. Degradation of most cell proteins requires their con-jugation to ubiquitin before hydrolysis by the 26S protea-some 6,13-16. This large complex contains the 20S proteasome as its proteolytic core6,14,16-18. This ubiquitin-dependent proteolytic pathway is implicated in MHC class I presentation11,12. γ-Inter-feron (γ-IFN), a stimulator of antigen presentation1, induces a subclass of proteasomes that contain two MHC-encoded subunits, LMP2 and 7 (refs 5-10). Here we show that γ-interferon alters the peptidase activities of the 20S and 268 proteasomes without affecting the rates of breakdown of proteins or of ubiquitinated proteins. By enhancing the expression of MHC genes, γ-IFN increases the proteasomes' capacity to cleave small peptides after hydrophobic and basic residues but reduces cleavage after acidic residues. Moreover, proteasomes of mutants lacking LMP sub-units show decreased rates of cleavage after hydrophobic and basic residues. Thus, γ-IFN and expression of these MHC genes should favour the production by proteasomes of the types of peptides found on MHC class I molecules, which terminate almost exclusively with hydrophobic or basic residues19.

Original languageEnglish (US)
Pages (from-to)264-267
Number of pages4
JournalNature
Volume365
Issue number6443
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

ASJC Scopus subject areas

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