title: Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity.
abstract: 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.
authors.affiliation: Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Wang
authors.forename: B M
authors.initials: BM
authors.lastname: Kessler
authors.forename: A
authors.initials: A
authors.lastname: Borodovsky
authors.forename: B F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: M
authors.initials: M
authors.lastname: Bogyo
authors.forename: H L
authors.initials: HL
authors.lastname: Ploegh
authors.forename: R
authors.initials: R
authors.lastname: Glas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020169:Caspases / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007700:Kinetics; D008223:Lymphoma; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000302:isolation & purification / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D014357:Trypsin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014452:Ubiquitins; D010447:Peptide Hydrolases; C028759:oligopeptidase; D014357:Trypsin; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex