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Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

  • Chiusolo, Valentina Department of Cell Physiology and Metabolism, University of Geneva, Switzerland -
  • Jacquemin, Guillaume Department of Cell Physiology and Metabolism, University of Geneva, Switzerland -
  • Bassoy, Esen Yonca Department of Cell Physiology and Metabolism, University of Geneva, Switzerland
  • Vinet, Laurent Department of Radiology and Medical Informatics, Geneva University Hospital, Geneva, Switzerland - Institute of Translational Molecular Imaging, University of Geneva, Switzerland
  • Liguori, Lavinia IBS/Groupe Channels, Grenoble, France
  • Walch, Michael Anatomy Unit, Department of Medicine, University of Fribourg, Switzerland
  • Kozjak-Pavlovic, Vera Biozentrum Department of Microbiology, Würzburg, Germany
  • Martinvalet, Denis Department of Cell Physiology and Metabolism, University of Geneva, Switzerland
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    24.03.2017
Published in:
  • Cell Death & Differentiation. - 2017, vol. 24, no. 4, p. 747–758
English We have found that granzyme B (GB)-induced apoptosis also requires reactive oxygen species resulting from the alteration of mitochondrial complex I. How GB, which does not possess a mitochondrial targeting sequence, enter this organelle is unknown. We show that GB enters the mitochondria independently of the translocase of the outer mitochondrial membrane complex, but requires instead Sam50, the central subunit of the sorting and assembly machinery that integrates outer membrane β- barrel proteins. Moreover, GB breaches the inner membrane through Tim22, the metabolite carrier translocase pore, in a mitochondrial heat-shock protein 70 (mtHsp70)-dependent manner. Granzyme A (GA) and caspase-3 use a similar route to the mitochondria. Finally, preventing GB from entering the mitochondria either by mutating lysine 243 and arginine 244 or depleting Sam50 renders cells more resistant to GB-mediated reactive oxygen species and cell death. Similarly, Sam50 depletion protects cells from GA-, GM- and caspase-3-mediated cell death. Therefore, cytotoxic molecules enter the mitochondria to induce efficiently cell death through a noncanonical Sam50-, Tim22- and mtHsp70-dependent import pathway.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/305555
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