Inhibition of Daxx-mediated apoptosis by heat shock protein 27

Heat shock protein 27 (HSP27) confers cellular protection against a variety of cytotoxic stresses and also against physiological stresses associated w ith growth arrest or receptor-mediated apoptosis. Phosphorylation modulates the activity of HSP27 by causing a major change in the supramolecular orga nization of the protein, which shifts from oligomers to dimers. Here we sho w that phosphorylated dimers of HSP27 interact with Daxx, a mediator of Fas -induced apoptosis, preventing the interaction of Daxx with both Ask1 and F as and blocking Daw-mediated apoptosis. No such inhibition was observed wit h an HSP27 phosphorylation mutant that is only expressed as oligomers or wh en apoptosis was induced by transfection of a Daxx mutant lacking its HSP27 binding domain. HSP27 expression had no effect on Fas-induced FADD- and ca spase-dependent apoptosis. However, HSP27 blocked Fas-induced translocation of Daxx from the nucleus to the cytoplasm and Fas-induced Daxx- and Ask1-d ependent apoptosis. The observations revealed a new level of regulation of the Fas pathway and suggest a mechanism for the phosphorylation-dependent p rotective function of HSP27 during stress and differentiation.