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Disruption of HSP90 function reverts tumor necrosis factor-induced necrosis to apoptosis

par Vanden Berghe, Tom;Kalai, Michaël ;Van Loo, Geert;Declercq, Wim;Vandenabeele, Peter
Référence The Journal of biological chemistry, 278, 8, page (5622-5629)
Publication Publié, 2003-02

Article révisé par les pairs

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Résumé :

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 κB kinase-α, inhibitor of κB kinase-β, and to a lesser extent the adaptors NF-κB essential modulator and tumor necrosis factor receptor-associated factor 2. As a consequence, NF-κB, 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.