ROLE OF PROTEASOMES IN ANTIGEN PRESENTATION

Recent studies have demonstrated that the proteasome, in addition to f unctioning in the complete degradation of cell proteins, is the source of most antigenic peptides presented to the immune system on major hi stocompatibility complex (MHC)-class I molecules. In this process, int racellular and viral proteins are degraded in the cytosol to 8- to 9-a mino acid fragments, which are then transported into the endoplasmic r eticulum, where they become associated with MHC-class I molecules and are thus delivered to the cell surface. A variety of evidence has show n that the proteasome and ATP-ubiquitin-dependent pathway are critical in this process: (1) In cells, selective inhibitors of proteasome fun ction inhibit the bulk of protein degradation and thus prevent the gen eration of peptides necessary for class I presentation and the appeara nce of MHC on the cell surface. (2) Mutations that block ubiquitin con jugation prevent the generation of an antigenic peptide. (3) Modificat ions that lead to rapid degradation of a protein by the ubiquitin path way enhance antigen presentation. (4) gamma-Interferon (gamma-IFN) ind uces new proteasome subunits, LMP2 and LMP7, encoded in the MHC region that are incorporated in place of constitutive proteasome subunits. T heir incorporation does not affect rates of protein breakdown but caus es changes in peptidase activities, i.e. they increase rates of cleava ge after basic and hydrophobic residues and decrease cleavage after ac idic residues. Transfections of cells with LMP2 or LMP7 cause similar changes in these peptidase activities as are caused by gamma-IFN. Thes e modifications in peptidase activities should enhance the production of those types of peptides which are preferentially transported into e ndoplasmic reticulum and selectively bound to MHC-class I molecules.