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Mitochondrial heat shock protein (HSP) 70 synergizes with HSP60 in transducing endothelial cell apoptosis induced by anti-HSP60 autoantibody

Jean-Eric Alard^*,,, Maryvonne Dueymes^*,,, Rizgar A. Mageed, Alain Saraux^*,,, Pierre Youinou^*,,,1 and Christophe Jamin^*,,

^* Université Européenne de Bretagne, Brest, France;

Université de Brest, EA 2216 Immunology and Pathology, IFR 148 ScInBioS, Brest, France;

Centre Hospitalier Universitaire Brest Hôpital Morvan, Brest, France; and

Bone and Joint Research Unit, William Harvey Research Institute, Barts and the London Queen Mary School of Medicine and Dentistry, London, UK

¹ Correspondence: Laboratory of Immunology, Brest University Medical School Hospital, 5 av Foch, BP 824, F29609 Brest Cedex, France. E-mail: youinou{at}univ-brest.fr

Heat shock protein (HSP) 60, up-regulated by endothelial cells (ECs) to resist stress, is the target of a subgroup of apoptosis-inducing anti-EC autoantibodies (Abs) in human vasculitides. Given that HSP60 is not a transmembrane protein, the mechanism by which these auto-Abs induces apoptosis is unclear. EC membrane proteins were analyzed using bidimensional electrophoresis and Far Western blot, and the HSP60 receptor was identified by mass spectrometry. Heat stress-dependent synthesis of HSP60 and receptor was examined by semiquantitative RT-PCR, and expression was examined by flow cytometry and indirect immunofluorescence. Interaction was demonstrated by coimmunoprecipitations. Lipid rafts were purified to evaluate specific localization, and the apoptotic response was investigated by blocking monoclonal Ab. Mitochondrial HSP70 (mtHSP70) was identified as an HSP60 receptor. Stress was required for ECs to up-regulate mRNA and express mtHSP70 on their surface. HSP60 and mtHSP70 colocalized and interacted within lipid rafts. They were associated with chemokine CC motif receptor 5 (CCR5), also induced at the mRNA and protein levels in stressed ECs. CCR5 was involved in the anti-HSP60-triggered apoptosis of ECs. These results provide new insights into the mechanism by which anti-EC auto-Abs from vasculitides induce apoptosis of ECs.—Alard, J.-E., Dueymes, M., Mageed, R. A., Saraux, A., Youinou, P., Jamin, C. Mitochondrial heat shock protein (HSP) 70 synergizes with HSP60 in transducing endothelial cell apoptosis induced by anti-HSP60 autoantibody.

Key Words: antibodies • stress • endothelium • vasculitis • cell surface interaction • CCR5

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