Abstract
Heat shock protein 25 (HSP25) interferes negatively with apoptosis through several pathways that involve its direct interaction with cytochrome c or Akt. Here we show that HSP25 inhibits protein kinase C (PKC) delta-mediated cell death through direct interaction. HSP25 binds to kinase-active PKCdelta to inhibit its kinase activity and translocation to the membrane, which results in reduced cell death. Deletion constructs of HSP25 and PKCdelta identified amino acids 90-103 of HSP25 and the C-terminal V5 region of PKCdelta as binding sites. In addition, the interaction between HSP25 and PKCdelta induced HSP25 phosphorylation at Ser-15 and Ser-86, and these phosphorylations permitted HSP25 release from PKCdelta. Based on these observations, we propose that after PKCdelta activation, HSP25 binds to the exposed V5 region of PKCdelta. This novel function of HSP25 accounts for its cytoprotective properties via the inhibition of PKCdelta and the enhancement of HSP25 phosphorylation.
Highlights
Small heat shock protein (HSP)1 has been suggested to protect cells against apoptotic cell death triggered by hyperthermia, ionizing radiation, oxidative stress, Fas ligand, and cytotoxic drugs [1,2,3,4,5]
Interaction between Heat shock protein 25 (HSP25) and the Catalytic Domain of protein kinase C (PKC)␦ and PKC␦ Kinase Activity Is Necessary for Its Interaction with HSP25—As HSP25 overexpression was found to inhibit PKC␦ activity in our previous study [14], and another HSP, HSP70, was reported to bind PKC [32], we examined possible binding between HSP25 and PKC␦
Immunoprecipitation revealed that the catalytic domain of PKC␦ (CAT), but not the regulatory domain of PKC␦ (REG), is an HSP25 binding target
Summary
Small heat shock protein (HSP) has been suggested to protect cells against apoptotic cell death triggered by hyperthermia, ionizing radiation, oxidative stress, Fas ligand, and cytotoxic drugs [1,2,3,4,5]. Phosphorylated HSP27 has been shown to bind an adaptor protein Daxx and to inhibit Fas-mediated apoptosis [9]. We reported recently that the radioprotective effect of HSP25 involves delayed cell growth [11, 12] and HSP25-mediated Mn-SOD gene expression [13, 14]. HSP25 overexpression down-regulates ERK1/2 expression, and HSP25-mediated ERK2 suppression is involved in HSP25-induced radioresistance and cell cycle delay [15]. Mizuno et al [26] showed that the kinase activity of a PKC␦ catalytic fragment during apoptosis may be a key participant in the late stages of apoptosis
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