title: Proteasome inhibition activates the mitochondrial pathway of apoptosis in human CD4+ T cells.
abstract: We have previously shown that inhibition of the proteolytic activity of the proteasome induces apoptosis and suppresses essential functions of activated human CD4(+) T cells, and we report now the detailed mechanisms of apoptosis following proteasome inhibition in these cells. Here we show that proteasome inhibition by bortezomib activates the mitochondrial pathway of apoptosis in activated CD4(+) T cells by disrupting the equilibrium of pro-apoptotic and anti-apoptotic proteins at the outer mitochondrial membrane (OMM) and by inducing the generation of reactive oxygen species (ROS). Proteasome inhibition leads to accumulation of pro-apoptotic proteins PUMA, Noxa, Bim and p53 at the OMM. This event provokes mitochondrial translocation of activated Bax and Bak homodimers, which induce loss of mitochondrial membrane potential (DeltaPsim). Breakdown of DeltaPsim is followed by rapid release of pro-apoptotic Smac/DIABLO and HtrA2 from mitochondria, whereas release of cytochrome c and AIF is delayed. Cytoplasmic Smac/DIABLO and HtrA2 antagonize IAP-mediated inhibition of partially activated caspases, leading to premature activation of caspase-3 followed by activation of caspase-9. Our data show that proteasome inhibition triggers the mitochondrial pathway of apoptosis by activating mutually independent apoptotic pathways. These results provide novel insights into the mechanisms of apoptosis induced by proteasome inhibition in activated T cells and underscore the future use of proteasome inhibitors for immunosuppression.
authors.affiliation: Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Berges
authors.forename: Heinrich
authors.initials: H
authors.lastname: Haberstock
authors.forename: Dominik
authors.initials: D
authors.lastname: Fuchs
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Sadeghi
authors.forename: Gerhard
authors.initials: G
authors.lastname: Opelz
authors.forename: Volker
authors.initials: V
authors.lastname: Daniel
authors.forename: Cord
authors.initials: C
authors.lastname: Naujokat
mesh_terms: D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D019281:Dimerization; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex