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Lysosomal protease pathways to apoptosis - Cleavage of Bid, not pro-caspases, is the most likely route

Stoka, Veronika; Turk, Boris; Schendel, Sharon L.; Kim, Tae-Hyoung; Cirman, Tina; Snipas, Scott J.; Ellerby, Lisa M.; Bredesen, Dale; Freeze, Hudson and Abrahamson, Magnus LU , et al. (2001) In Journal of Biological Chemistry 276(5). p.3149-3157
Abstract
We investigated the mechanism of lysosome-mediated cell death using purified recombinant pro-apoptotic proteins, and cell-free extracts from the human neuronal progenitor cell line NT2, Potential effectors were either isolated lysosomes or purified lysosomal proteases. Purified lysosomal cathepsins B, H, K, L, S, and X or an extract of mouse lysosomes did not directly activate either recombinant caspase zymogens or caspase zymogens present in an NT2 cytosolic extract to any significant extent. In contrast, a cathepsin L-related protease from the protozoan parasite Trypanosana cruzi, cruzipain, showed a measurable caspase activation rate. This demonstrated that members of the papain family can directly activate caspases but that mammalian... (More)
We investigated the mechanism of lysosome-mediated cell death using purified recombinant pro-apoptotic proteins, and cell-free extracts from the human neuronal progenitor cell line NT2, Potential effectors were either isolated lysosomes or purified lysosomal proteases. Purified lysosomal cathepsins B, H, K, L, S, and X or an extract of mouse lysosomes did not directly activate either recombinant caspase zymogens or caspase zymogens present in an NT2 cytosolic extract to any significant extent. In contrast, a cathepsin L-related protease from the protozoan parasite Trypanosana cruzi, cruzipain, showed a measurable caspase activation rate. This demonstrated that members of the papain family can directly activate caspases but that mammalian lysosomal members of this family may have been negatively selected for caspase activation to prevent inappropriate induction of apoptosis, Given the lack of evidence for a direct role in caspase activation by lysosomal proteases, we hypothesized that an indirect mode of caspase activation may involve the Bcl-2 family member Bid. In support of this, Bid was cleaved in the presence of lysosomal extracts, at a site six residues downstream from that seen for pathways involving capase 8, Incubation of mitochondria with Bid that had been cleaved by lysosomal extracts resulted in cytochrome c release. Thus, cleavage of Bid may represent a mechanism by which proteases that have leaked from the lysosomes can precipitate cytochrome c release and subsequent caspase activation. This is supported by the finding that cytosolic extracts from mice ablated in the bid gene are impaired in the ability to release cytochrome c in response to lysosome extracts, Together these data suggest that Bid represents a sensor that allows cells to initiate apoptosis in response to widespread adventitious proteolysis. (Less)
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Journal of Biological Chemistry
volume
276
issue
5
pages
3149 - 3157
publisher
ASBMB
external identifiers
  • wos:000166784900024
  • scopus:0035793580
ISSN
1083-351X
DOI
10.1074/jbc.M008944200
language
English
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f421b897-33a3-4c2f-8eb6-2413326b400c (old id 1119662)
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2008-07-15 10:53:16
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@article{f421b897-33a3-4c2f-8eb6-2413326b400c,
  abstract     = {We investigated the mechanism of lysosome-mediated cell death using purified recombinant pro-apoptotic proteins, and cell-free extracts from the human neuronal progenitor cell line NT2, Potential effectors were either isolated lysosomes or purified lysosomal proteases. Purified lysosomal cathepsins B, H, K, L, S, and X or an extract of mouse lysosomes did not directly activate either recombinant caspase zymogens or caspase zymogens present in an NT2 cytosolic extract to any significant extent. In contrast, a cathepsin L-related protease from the protozoan parasite Trypanosana cruzi, cruzipain, showed a measurable caspase activation rate. This demonstrated that members of the papain family can directly activate caspases but that mammalian lysosomal members of this family may have been negatively selected for caspase activation to prevent inappropriate induction of apoptosis, Given the lack of evidence for a direct role in caspase activation by lysosomal proteases, we hypothesized that an indirect mode of caspase activation may involve the Bcl-2 family member Bid. In support of this, Bid was cleaved in the presence of lysosomal extracts, at a site six residues downstream from that seen for pathways involving capase 8, Incubation of mitochondria with Bid that had been cleaved by lysosomal extracts resulted in cytochrome c release. Thus, cleavage of Bid may represent a mechanism by which proteases that have leaked from the lysosomes can precipitate cytochrome c release and subsequent caspase activation. This is supported by the finding that cytosolic extracts from mice ablated in the bid gene are impaired in the ability to release cytochrome c in response to lysosome extracts, Together these data suggest that Bid represents a sensor that allows cells to initiate apoptosis in response to widespread adventitious proteolysis.},
  author       = {Stoka, Veronika and Turk, Boris and Schendel, Sharon L. and Kim, Tae-Hyoung and Cirman, Tina and Snipas, Scott J. and Ellerby, Lisa M. and Bredesen, Dale and Freeze, Hudson and Abrahamson, Magnus and Bromme, Dieter and Krajewski, Stanislaw and Reed, John C. and Yin, Xiao-Ming and Turk, Vito and Salvesen, Guy S.},
  issn         = {1083-351X},
  language     = {eng},
  number       = {5},
  pages        = {3149--3157},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Lysosomal protease pathways to apoptosis - Cleavage of Bid, not pro-caspases, is the most likely route},
  url          = {http://dx.doi.org/10.1074/jbc.M008944200},
  volume       = {276},
  year         = {2001},
}