GAMMA-INTERFERON AND EXPRESSION OF MHC GENES REGULATE PEPTIDE HYDROLYSIS BY PROTEASOMES

THE presentation of intracellular proteins to the immune system requir es 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 par ticles, which contain multiple proteolytic activities5-14 including di stinct 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 conjugation to ubiquitin before hydr olysis by the 26S proteasome6,13-16. This large complex contains the 2 0S proteasome as its proteolytic core6,14,16-18. This ubiquitin-depend ent proteolytic pathway is implicated in MHC class I presentation11,12 . Gamma-interferon (gamma-IFN, a stimulator of antigen presentation1, induces a subclass of proteasomes that contain two MHC-encoded subunit s, LMP2 and 7 (refs 5-10). Here we show that gamma-interferon alters t he peptidase activities of the 20S and 26S proteasomes without affecti ng the rates of breakdown of proteins or of ubiquitinated proteins. By enhancing the expression of MHC genes, gamma-IFN increases the protea somes' capacity to cleave small peptides after hydrophobic and basic r esidues but reduces cleavage after acidic residues. Moreover, proteaso mes of mutants lacking LMP subunits show decreased rates of cleavage a fter hydrophobic and basic residues. Thus, gamma-IFN and expression of these MHC genes should favour the production by proteasomes of the ty pes of peptides found on MHC class I molecules, which terminate almost exclusively with hydrophobic or basic residues19.