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  • Original Paper
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AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis

Abstract

Cyclophilin A (CypA) was determined to interact with apoptosis-inducing factor (AIF) by mass spectroscopy, coimmunoprecipitation, pull-down assays, and molecular modeling. During the initial, caspase-independent stage of chromatin condensation that accompanies apoptosis, AIF and CypA were found to coimmunolocalize in the nucleus. Recombinant AIF and CypA proteins synergized in vitro in the degradation of plasmid DNA, as well as in the capacity to induce DNA loss in purified nuclei. The apoptogenic cooperation between AIF and CypA did not rely on the CypA peptidyl-prolyl cis–trans isomerase activity. In Cyp-expressing cells, AIF overexpression augmented apoptotic chromatinolysis. The AIF-dependent large-scale DNA fragmentation was less pronounced in CypA knockout cells as compared to controls. AIF mutants lacking the CypA-binding domain were inefficient apoptosis sensitizers in transfection experiments. Moreover, AIF failed to sensitize CypA knockout cells to apoptosis induction, and this defect in the AIF response was reversed by reintroduction of the CypA gene into CypA-deficient cells. In summary, AIF and CypA collaborate in chromatinolysis.

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Abbreviations

AIF:

apoptosis-inducing factor

BSA:

bovine serum albumin

Cyp-A:

cyclophilin A

Cyt c:

cytochrome c

FCS:

fetal calf serum

Hsp70:

heat shock protein 70

Hsc70:

heat shock cognate protein 70

STS:

staurosporin

Z-VAD.fmk:

N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

References

  • Aloy P, Moont G, Gabb HA, Querol E, Aviles FX and Sternberg MJE . (1998). Proteins, 33, 535–549.

  • Ansari H, Greco G and Luban J . (2002). Mol. Cell. Biol., 22, 6993–7003.

  • Arnoult D, Estaquier J, Tatischeff I, Tissier JP, Grodet A, Dellinger M, Kahn A, Ameisen JC and Petit PX . (2001). Mol. Biol. Cell, 12, 3016–3030.

  • Arnoult D, Parone P, Martinou J-C, Antonsson B, Estaquier J and Ameisen JC . (2002). J. Cell Biol., 59, 923–929.

  • Bergsmedh A, Szeles A, Henriksson M, Bratt A, Folkman MJ, Spetz AL and Holmgren L . (2001). Proc. Natl. Acad. Sci. USA, 98, 6407–6411.

  • Bergsmedh A, Szeles A, Spetz AL and Holmgren L . (2002). Cancer Res., 62, 575–579.

  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN and PE B . (2000). Nucleic Acids Res., 28, 235–242.

  • Blomgren K, Zhu C, Hallin U and Hagberg H . (2003). Biochem. Biophys. Res. Commun., 304, 551–559.

  • Braaten D and Luban J . (2001). EMBO J., 20, 1300–1309.

  • Cande C, Cecconi F, Dessen P and Kroemer G . (2002). J. Cell Sci., 115, 4727–4734.

  • Castedo M, Ferri K, Roumier T, Metivier D, Zamzami N and Kroemer G . (2002). J. Immunol. Methods, 265, 39–47.

  • Castedo M, Ferri KF, Blanco J, Roumier T, Larochette N, Barretina J, Amendola A, Nardacci R, Metivier D, Este JA, Piacentini M and Kroemer G . (2001). J. Exp. Med., 194, 1097–1110.

  • Colgan S, Asmal M and Luban J . (2000). Genomics, 68, 167–178.

  • Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Park DS, Dawson TM, Kroemer G and Slack RS . (2002). J. Cell Biol., 158, 507–517.

  • Daugas E, Susin SA, Zamzami N, Ferri K, Irinopoulos T, Larochette N, Prevost MC, Leber B, Andrews D, Penninger J and Kroemer G . (2000). FASEB J., 14, 729–739.

  • de la Taille A, Chen MW, Burchardt M, Chopin DK and Buttyan R . (1999). Cancer Res., 59, 5461–5463.

  • Dumont C, Durrbach A, Bidere N, Rouleau M, Kroemer G, Bernard G, Susin SA and Senik A . (2000). Blood, 96, 1030–1038.

  • Enari M, Sakahira H, Yokoyoma H, Okawa K, Iwamtsu A and Nagata S . (1998). Nature, 391, 43–50.

  • Ferri KF, Jacotot E, Blanco J, Esté JA, Zamzami A, Susin SA, Brothers G, Reed JC, Penninger JM and Kroemer G . (2000). J. Exp. Med., 192, 1081–1092.

  • Goodford PJ . (1985). J. Med. Chem., 28, 849–857.

  • Gurbuxani S, Schmitt E, Cande C, Parcellier A, Hamman A, Daugas E, Kouranti I, Spahr C, Pance A, Kroemer G and Garrido C . (2003). Oncogene, 22, 6669–6678.

  • Hengartner MO . (2000). Nature, 407, 770–776.

  • Hisatomi T, Sakamoto T, Murata T, Yamanaka I, Oshima Y, Hata Y, Ishibashi T, Inomata J, Susin SA and Kroemer G . (2001). Am. J. Pathol., 158, 1271–1278.

  • Jackson RM, Gabb HA and Sternberg MJ . (1998). J. Mol. Biol., 276, 265–285.

  • Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CYJ, Sasaki T, Elia AJ, Cheng H-YM, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong Y-Y, Zuñiga-Pflücker JC, Kroemer G and Penninger JM . (2001). Nature, 410, 549–554.

  • Ke H . (1992). J. Mol. Biol., 228, 539–550.

  • Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT and Ackerman SL . (2002). Nature, 419, 367–374.

  • Li LY, Luo X and Wang X . (2001). Nature, 412, 95–99.

  • Loeffler M, Daugas E, Susin SA, Zamzami N, Métivier D, Nieminen A-L, Brothers G, Penninger JM and Kroemer G . (2001). FASEB J., 15, 758–767.

  • Loeffler M and Kroemer G . (2000). Exp. Cell Res., 256, 19–26.

  • Lorenzo K, Susin SA and Kroemer G . (2000). Meth. Enzymol., 322, 198–201.

  • Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Rémy R, Xie Z-H, Reed JC and Kroemer G . (1998). J. Exp. Med., 187, 1261–1271.

  • Miramar MD, Costantini P, Ravagnan L, Saraiva LM, Haouzi D, Brothers G, Penninger JM, Peleato ML, Kroemer G and Susin SA . (2001). J. Biol. Chem., 276, 16391–16398.

  • Montague JW, Gaido ML, Frye C and Cidlowski JA . (1994). J. Biol. Chem., 269, 18877–18880.

  • Montague JW, Hughes FM and Cidlowski JA . (1997). J. Biol. Chem., 272, 6677–6684.

  • Nicholls A and Honig B . (1991). J. Comput. Chem., 12, 435–445.

  • Nicholls A, Sharp K and Honig B . (1991). Prot. Struct. Funct. Gen., 11, 281–287.

  • Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jaattela M, Penninger JM, Garrido C and Kroemer G . (2001). Nat. Cell Biol., 3, 839–843.

  • Sakahira H, Enari M and Nagata S . (1998). Nature, 391, 96–99.

  • Schmitt E, Parcellier A, Gurbuxani S, Cande C, Hamman A, Morales MC, Kroemer G, Giordanetto F, Jaattela M, Pance A, Penninger JM, Kroemer G and Garrido C . (2003). Cancer Research, in press.

  • Spahr CS, Susin SA, Bures EJ, Robinson JH, Davis MT, McGinley MD, Kroemer G and Patterson S . (2000). Electrophoresis, 21, 1635–1650.

  • Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, Costantini P, Ferri KF, Irinopoulou T, Prévost M-C, Brothers G, Mak TW, Penninger J, Earnshaw WC and Kroemer G . (2000). J. Exp. Med., 192, 571–579.

  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM and Kroemer G . (1999). Nature, 397, 441–446.

  • Susin SA, Zamzami N, Larochette N, Dallaporta B, Marzo I, Brenner C, Hirsch T, Petit PX, Geuskents M and Kroemer G . (1997). Exp. Cell Res., 236, 397–403.

  • Wang X, Yang C, Chai J, Shi Y and Xue D . (2002). Science, 298, 1587–1592.

  • Widlak P, Li LY, Wang X and Garrard WT . (2001). J. Biol. Chem., 276, 48404–48409.

  • Wyllie AH . (1980). Nature, 284, 555–556.

  • Wyllie AH and Golstein P . (2001). Proc. Natl. Acad. Sci. USA, 98, 11–13.

  • Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G and Wu H . (2002). Nat. Struct. Biol., 9, 680–684.

  • Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM and Dawson VL . (2002). Science, 297, 259–263.

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Acknowledgements

We thank Didier Métivier, Nathanael Larochette (CNRS, Villejuif, France) for assistance. This work has been supported by a special grant from LNC, grants from ANRS, FRM, European Commission (QLG1-CT-1999-00739 and Contract No QLK3-CT-20002-01956) (to GK), and a grant from the NIH (AI 36199) to JL. CC received a fellowship from ARC.

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Correspondence to Guido Kroemer.

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Candé, C., Vahsen, N., Kouranti, I. et al. AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene 23, 1514–1521 (2004). https://doi.org/10.1038/sj.onc.1207279

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