Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol

J Cell Biol. 2003 Mar 31;160(7):1115-27. doi: 10.1083/jcb.200212059.

Abstract

Stimulation of cell surface death receptors activates caspase-8, which targets a limited number of substrates including BAP31, an integral membrane protein of the endoplasmic reticulum (ER). Recently, we reported that a caspase-resistant BAP31 mutant inhibited several features of Fas-induced apoptosis, including the release of cytochrome c (cyt.c) from mitochondria (Nguyen, M., D.G. Breckenridge, A. Ducret, and G.C. Shore. 2000. Mol. Cell. Biol. 20:6731-6740), implicating ER-mitochondria crosstalk in this pathway. Here, we report that the p20 caspase cleavage fragment of BAP31 can direct pro-apoptotic signals between the ER and mitochondria. Adenoviral expression of p20 caused an early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and mitochondrial recruitment of Drp1, a dynamin-related protein that mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network. Inhibition of Drp1 or ER-mitochondrial Ca2+ signaling prevented p20-induced fission of mitochondria. p20 strongly sensitized mitochondria to caspase-8-induced cyt.c release, whereas prolonged expression of p20 on its own ultimately induced caspase activation and apoptosis through the mitochondrial apoptosome stress pathway. Therefore, caspase-8 cleavage of BAP31 at the ER stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cyt.c in response to this initiator caspase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apoptosis*
  • CHO Cells
  • Calcium / metabolism*
  • Caspases / metabolism*
  • Cell Line
  • Cricetinae
  • Cytochrome c Group / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Cytosol / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • HSP20 Heat-Shock Proteins
  • HeLa Cells
  • Heat-Shock Proteins*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria / physiology*
  • Models, Biological
  • Muscle Proteins / metabolism
  • Rats
  • Signal Transduction
  • Tumor Cells, Cultured
  • Utrophin
  • fas Receptor / metabolism

Substances

  • BCAP31 protein, human
  • Cytochrome c Group
  • Cytoskeletal Proteins
  • HSP20 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Membrane Proteins
  • Muscle Proteins
  • Utrophin
  • fas Receptor
  • Hspb6 protein, rat
  • Caspases
  • Calcium