The proteasome regulates receptor-mediated endocytosis of interleukin-2

Recent studies have increasingly implicated the proteasome in the regulation of cell surface receptors. In the present study, we investigated the role of the proteasome for ligand-dependent endocytosis and degradation of the interleukin-2 (IL-S)-interleukin-2 receptor (IL-BR) complex. Proteasome inhibitors impaired internalization of IL-2IL-2R and prevented the lysosomal degradation of this cytokine. Based on time-course studies, proteasome activity is primarily required after initial endocytosis of the IL-2 IL-2R. Proteasome function was also necessary for the lysosomal degradation of IL-2 internalized by IL-BR that were comprised of cytoplasmic tailless beta- or alpha -subunits, suggesting that the target protein for the proteasome is independent of either the cytoplasmic tail of the IL-BR beta- or gammac-subunits and their associated signaling components. Therefore, a functional proteasome is required for optimal endocytosis of the IL-SR/ligand complex and is essential for the subsequent lysosomal degradation of IL-2, possibly by regulating trafficking to the lysosome.