ESSENTIAL ROLE FOR CATHEPSIN-S IN MHC CLASS-II - ASSOCIATED INVARIANTCHAIN PROCESSING AND PEPTIDE LOADING

Destruction of ii by proteolysis is required for MHC class II molecule s to bind antigenic peptides, and for transport of the resulting compl exes to the cell surface. The cysteine protease cathepsin S is highly expressed in spleen, lymphocytes, monocytes, and other class Ii-positi ve cells, and is inducible with interferon-gamma. Specific inhibition of cathepsin S in B lymphoblastoid cells prevented complete proteolysi s of ii, resulting in accumulation of a class II-associated 13 kDa ii fragment in vivo. Consequently, the formation of SDS-stable complexes was markedly reduced. Purified cathepsin S, but not cathepsin B, H, or D, specifically digested Ii from alpha beta li trimers, generating al pha beta-CLIP complexes capable of binding exogenously added peptide i n vitro. Thus, cathepsin S is essential in B cells for effective ii pr oteolysis necessary to render class II molecules competent for binding peptides.