title: The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP).
abstract: Programmed cell death (apoptosis) is crucial for thymocyte development. We analyzed the role of the ubiquitin (Ub)-proteasome pathway in dexamethasone-triggered and TCR-mediated apoptosis in fetal thymic organ culture (FTOC). Proteasome activity was increased in apoptotic thymocytes, as visualized by active-site labeling of proteasomal beta subunits. The activity of deubiquitinating enzymes in murine apoptotic thymocytes was likewise examined by active-site labeling. We show that the deubiquitinating enzyme USP7 (HAUSP) is proteolytically processed upon dexamethasone-, gamma-irradiation-, and antigen-induced cell death. Such processing of HAUSP does not occur in caspase 3-/- thymocytes, or upon pretreatment of wild type thymocytes with the general caspase inhibitor ZVAD-fmk. Thus, our results suggest that thymocyte apoptosis leads to modification of deubiquitinating enzymes by caspase activity and may provide an additional link between the ubiquitin-proteasome pathway and the caspase cascade during programmed cell death.
authors.affiliation: Department of Pathology, Harvard Medical School, Building D2, Room 137, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.forename: Madelon M
authors.initials: MM
authors.lastname: Maurice
authors.forename: René
authors.initials: R
authors.lastname: Maehr
authors.forename: Margo H
authors.initials: MH
authors.lastname: Furman
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000502:physiology*; D009924:Organ Culture Techniques; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D009097:Multienzyme Complexes; D025801:Ubiquitin; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003907:Dexamethasone; D010450:Endopeptidases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; C506444:CASP12 protein, human; C505407:CASP3 protein, human; C506440:Casp12 protein, mouse; C505409:Casp3 protein, mouse; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex