Disruption of HSP90 function reverts tumor necrosis factor-induced necrosis to apoptosis.
Triggering tumor necrosis factor receptor-1 (TNFR1) induces apoptosis in various cell lines. In contrast, stimulation of TNFR1 in L929sA leads to necrosis. Inhibition of HSP90, a chaperone for many kinases, by geldanamycin or radicicol shifted the response of L929sA cells to TNF from necrosis to apoptosis. This shift was blocked by CrmA but not by BCL-2 overexpression, suggesting that it occurred through activation of procaspase-8. Geldanamycin pretreatment led to a proteasome-dependent decrease in the levels of several TNFR1-interacting proteins including the kinases receptor-interacting protein, inhibitor of kappa B kinase-alpha, inhibitor of kappa B kinase-beta, and to a lesser extent the adaptors NF-kappaB essential modulator and tumor necrosis factor receptor-associated factor 2. As a consequence, NF-kappa B, p38MAPK, and JNK activation were abolished. No significant decrease in the levels of mitogen-activated protein kinases, adaptor proteins TNFR-associated death domain and Fas-associated death domain, or caspase-3, -8, and -9 could be detected. These results suggest that HSP90 client proteins play a crucial role in necrotic signaling. We conclude that inhibition of HSP90 may alter the composition of the TNFR1 complex, favoring the caspase-8-dependent apoptotic pathway. In the absence of geldanamycin, certain HSP90 client proteins may be preferentially recruited to the TNFR1 complex, promoting necrosis. Thus, the availability of proteins such as receptor-interacting protein, Fas-associated death domain, and caspase-8 can determine whether TNFR1 activation will lead to apoptosis or to necrosis.
Vanden Berghe
Tom
T
Molecular Signaling and Cell Death Unit, Department of Molecular Biomedical Research, VIB, Gent University, B-9000 Gent, Belgium.
Kalai
Michael
M
van Loo
Geert
G
Declercq
Wim
W
Vandenabeele
Peter
P
D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005354:Fibrosarcoma; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D047029:Lactams, Macrocyclic; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009336:Necrosis; D011809:Quinones / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C001277:geldanamycin