Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor

Gurbuxani, Sandeep; Schmitt, Élise; Candé, Céline; Parcellier, Arnaud; Hammann, Arlette; Daugas, Éric; Kouranti, Ilektra; Spahr, Chris; Pance, Alena; Kroemer, Guido; Garrido, Carmen

doi:10.1038/sj.onc.1206794

Cited by 251 publications

(204 citation statements)

References 29 publications

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“…RAC3 is physically associated with AIF in a protein complex containing the Hsp90, the immunophilin (FKBP52) and the microtubule-associated motor protein dynein It has been previously reported that H 2 O 2 -induced cell death involves the release of AIF from mitochondria and its import to the nucleus (Susin et al, 1999;Arnoult et al, 2002) and that Hsp70 specifically interacts with AIF and antagonizes apoptosis (Ravagnan et al, 2001;Gurbuxani et al, 2003). In addition, it is well known that Hsp70 is usually associated with Hsp90, which is involved in the regulation of signaling protein function and trafficking together with immunophilins and the microtubule-associated motor protein dynein (Pratt and Toft, 2003;Galigniana et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

et al. 2007

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The p160 nuclear receptor co-activators represent a family of molecules, which are recruited by steroid nuclear receptors as well as other transcription factors that are overexpressed in several tumors. We investigated the role of one member of this family on the sensitivity of cells to apoptosis. We observed that overexpression of the RAC3 (receptor-associated co-activator-3) p160 co-activator inhibits hydrogen peroxide-induced cell death in human embryonic kidney 293 (HEK293) cells. The mechanism involves the activation of anti-apoptotic pathways mediated through enhanced nuclear factor kappa B (NFjB) activity, inhibition of caspase-9 activation, diminished apoptotic-inducing factor (AIF) nuclear localization and a change in the activation pattern of several kinases, including an increase in both AKT and p38 kinase activities, and inhibition of ERK2. Moreover, RAC3 has been found associated with a protein complex containing AIF, Hsp90 and dynein, suggesting a role for the coactivator in the cytoplasmatic nuclear transport of these proteins associated with cytoskeleton. These results demonstrate that there are several molecular pathways that could be affected by their overexpression, including those not restricted to steroid regulation or the nuclear action of co-activators, which results in diminished sensitivity to apoptosis. Furthermore, this could represent one mechanism by which co-activators contribute to tumor development.

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Section: Resultsmentioning

confidence: 99%

The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

et al. 2007

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“…Caspase-8 and -9 activation was demonstrated by the measurement of caspase enzymatic activity and pro-caspase cleavage, and the inhibition results obtained with caspase-8 (Z-IETD-FMK)-and caspase-9 (Z-LEHD-FMK)-specific peptide inhibitors, and with biological HSV2-R1, and hsp70 inhibitors. HSV2-R1 blocks the activation of caspase-8 by an unknown mechanism [24], whereas hsp70 blocks the caspase-9-associated apoptotic process by inhibiting the release of cytochrome c from mitochondria, or by a yetto-be-characterized mechanism that occurs downstream of caspase-9 activation [12,21,30]. The facts that both caspase-8 and -9 were activated upon NS3∆50 expression following AdV infection, and that the BVDV NS3∆50-induced apoptosis correlated with cytochrome c release, suggest that caspase-8 likely acts indirectly at the mitochondria level, resulting in the release of cytochrome c from the mitochondria, and downstream activation of caspase-9 and effector caspases, rather than directly activating caspase-3 [38].…”

Section: Discussionmentioning

confidence: 99%

The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation

2005

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-The bovine viral diarrhea virus (BVDV) strains exist as two biotypes, cytopathic (cp) and noncytopathic (ncp), according to their effects on tissue culture cells. It has been previously reported that cell death associated to cp BVDV in vitro is mediated by apoptosis. Here, experiments were conducted to determine the involvement of the NS3 protein in the induction of apoptosis. The NS3-and NS3∆50 (deleted from the NH2-terminal 50 amino acids)-cDNA encoding sequences of BVDV NADL cp reference strain were cloned into adenoviral vectors (AdV) from which the BVDV gene of interest could be expressed from a tetracycline-responsive promoter. A549tTA cells infected in vitro with NS3 or NS3∆50-expressing AdV showed cytopathic changes characterized by cell rounding and detachment, and nucleus chromatin condensation. DNA fragmentation assays, cytochrome c release, and activation of cellular caspases performed on these infected cells clearly correlated with the observed cytopathic changes with apoptosis. The BVDV NS3∆50-induced apoptotic process was inhibited by caspase-8-and -9-specific peptide inhibitors (Z-IETD-FMK and Z-LEHD-FMK). Furthermore, apoptosis was inhibited in cells expressing the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase (HSV2-R1) or hsp70, two proteins which are known to inhibit apoptosis associated with caspase-8 activation and cytochrome c release-dependent caspase-9 activation, respectively. Given that HSV2-R1, a specific inhibitor of the caspase-8 activation pathway, efficiently suppressed apoptosis and also prevented caspase-9 activation, the overall results indicate that the BVDV NS3/NS3∆50 induces apoptosis initiated by caspase-8 activation and subsequent cytochrome c release-dependent caspase-9 activation. bovine viral diarrhea virus / NS3 protein / apoptosis / caspases

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“…Triton-soluble proteins contained in rat brain extracts or in nuclear HeLa extracts were retained on these columns, eluted on an NaCl gradient beyond 500 mM NaCl and concentrated by buffer exchange, as described in detail by Gurbuxani et al The proteins were denatured, reduced, alkylated, subjected to proteolysis with trypsin, and then identified by LC-MS/MS, as previously described (Gurbuxani et al, 2003).…”

Section: Yeast Chronological Agingmentioning

confidence: 99%

“…We found that AIF binds to heat shock protein 70 (HSP70) and that this interaction can prevent AIF from translocating to the nucleus (Gurbuxani et al, 2003), where it exerts its proapoptotic action. This neutralizing interaction has been confirmed in vivo (Matsumori et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Physical interaction of apoptosis-inducing factor with DNA and RNA

et al. 2005

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein, which upon apoptosis induction translocates to the nucleus where it interacts with DNA by virtue of positive charges clustered on the AIF surface. Here we show that the AIF interactome, as determined by mass spectroscopy, contains a large panel of ribonucleoproteins, which apparently bind to AIF through the RNA moiety. However, AIF is devoid of any detectable RNAse activity both in vitro and in vivo. Recombinant AIF can directly bind to DNA as well as to RNA. This binding can be visualized by electron microscopy, revealing that AIF can condense DNA, showing a preferential binding to singlestranded over double-stranded DNA. AIF also binds and aggregates single-stranded and structured RNA in vitro. Single-stranded poly A, poly G and poly C, as well doublestranded A/T and G/C RNA competed with DNA for AIF binding with a similar efficiency, thus corroborating a computer-calculated molecular model in which the binding site within AIF is the same for distinct nucleic acid species, without a clear sequence specificity. Among the preferred electron donors and acceptors of AIF, nicotine adenine dinucleotide phosphate (NADP) was particularly efficient in enhancing the generation of higher-order AIF/ DNA and AIF/RNA complexes. Altogether, these data support a model in which a direct interaction of AIF contributes to the compaction of nucleic acids within apoptotic cells.

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Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor

Cited by 251 publications

References 29 publications

The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation

Physical interaction of apoptosis-inducing factor with DNA and RNA

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