Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity

Cytosolic proteolysis is carried out predominantly by the proteasome. We sh ow that a large oligopeptidase, tripeptidylpeptidase II (TPPII), can compen sate for compromised proteasome activity. Overexpression of TPPII is suffic ient to prevent accumulation of polyubiquitinated proteins and allows survi val of EL-4 cells at otherwise lethal concentrations of the covalent protea some inhibitor NLVS (NIP-leu-leu-leu-vinylsulfone). Elevated TPPII activity also partially restores peptide loading of MHC molecules. Purified proteas omes from adapted cells lack the chymotryptic-like activity, but still degr ade longer peptide substrates via residual activity of their Z subunits. Ho wever, growth of adapted cells depends on induction of other proteolytic ac tivities. Therefore, cytosolic oligopeptidases such as TPPII normalize rate s of intracellular protein breakdown required for normal cellular function and viability.