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Interaction between Hsp70 and bis(monoacylglycero)phosphate stabilizes lysosomes and promotes cell survival

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Lysosomal membrane permeabilization is an evolutionarily conserved hallmark of stress-induced cell death. Here we show that the major stress-inducible heat shock protein 70 (Hsp70) enhances cell survival by stabilizing lysosomes through a pH-dependent high affinity binding to an endo-lysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP; also referred to as lysobisphosphatidic acid). The positively charged ATPase domain of Hsp70 is responsible for the binding but the substrate-binding domain is also required for effective stabilization of lysosomes. Importantly, the cytoprotective effect can be obtained by endocytic delivery of recombinant Hsp70 and specifically reverted by extra cellular administration of BMP antibodies or Hsp70 inhibitors. Thus, this protein-lipid interaction opens exciting possibilities for the development of cytoprotective and cytotoxic lysosome-specific therapies for the treatment of degenerative diseases and cancer, respectively.
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Document Type: Abstract

Affiliations: 1: Institute for Chemistry, Humboldt University, D-10099 Berlin, Germany 2: Helsinki Biophysics & Biomembrane Group, Institute of Biomedicine, University of Helsinki, FIN-00014 Helsinki, Finland 3: International Institute of Molecular and Cell Biology, 02–109 Warsaw, Poland 4: INSERM U-517, Faculty of Medicine and Pharmacy, University of Dijon, 21017 Dijon, France 5: Department of Biochemistry, University of Geneva, 1211 Geneva 4, Switzerland 6: Kekule-Institute for Organic Chemistry and Biochemistry, University of Bonn, D-53121 Bonn, Germany 7: Afd. for Apoptosis og Center for Genotoxisk Stress, Institut for Biologisk Kræftforskning, Kræftens Bekæmpelse, Strandboulevarden 49, 2100 København Ø, Danmark

Publication date: May 1, 2008

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