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Cytosolic proteolysis is carried out predominantly by the proteasome. We show that a large oligopeptidase, tripeptidylpeptidase II (TPPII), can compensate for compromised proteasome activity. Overexpression of TPPII is sufficient to prevent accumulation of polyubiquitinated proteins and allows survival of EL-4 cells at otherwise lethal concentrations of the covalent proteasome inhibitor NLVS (NIP-leu-leu-leu-vinylsulfone). Elevated TPPII activity also partially restores peptide loading of MHC molecules. Purified proteasomes from adapted cells lack the chymotryptic-like activity, but still degrade longer peptide substrates via residual activity of their Z subunits. However, growth of adapted cells depends on induction of other proteolytic activities. Therefore, cytosolic oligopeptidases such as TPPII normalize rates of intracellular protein breakdown required for normal cellular function and viability.

Original publication

DOI

10.1073/pnas.180328897

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

29/08/2000

Volume

97

Pages

9990 - 9995

Keywords

Amino Acid Sequence, Animals, Caspases, Cysteine Endopeptidases, Cytosol, Histocompatibility Antigens Class I, Kinetics, Lymphoma, Mice, Molecular Sequence Data, Multienzyme Complexes, Peptide Fragments, Peptide Hydrolases, Proteasome Endopeptidase Complex, Recombinant Proteins, Substrate Specificity, Transfection, Trypsin, Tumor Cells, Cultured, Ubiquitins