Letter abstract
Nature Cell Biology 8, 72 - 77 (2005)
Published online: 18 December 2005 | doi:10.1038/ncb1340
In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis
Shine Tu1, Gavin P. McStay1,2, Louis-Martin Boucher3, Tak Mak3, Helen M. Beere1,2,4 & Douglas R. Green1,2,4
Activation of 'initiator' (or 'apical') caspases-2, -8 or -9 (refs 1–3) is crucial for induction of apoptosis. These caspases function to activate executioner caspapses that, in turn, orchestrate apoptotic cell death. Here, we show that a cell-permeable, biotinylated pan-caspase inhibitor (bVAD–fmk) both inhibited and 'trapped' the apical caspase activated when apoptosis was triggered. As expected, only caspase-8 was trapped in response to ligation of death receptors, whereas only caspase-9 was trapped in response to a variety of other apoptosis-inducing agents. Caspase-2 was exclusively activated in heat shock-induced apoptosis. This activation of caspase-2 was also observed in cells protected from heat-shock-induced apoptosis by Bcl-2 or Bcl-xL. Reduced sensitivity to heat-shock-induced death was observed in caspase-2-/- cells. Furthermore, cells lacking the adapter molecule RAIDD failed to activate caspase-2 after heat shock treatment and showed resistance to apoptosis in this setting. This approach unambiguously identifies the apical caspase activated in response to apoptotic stimuli, and establishes caspase-2 as a proximal mediator of heat shock-induced apoptosis.
- Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121, USA.
- Current Address: St Jude Children's Research Hospital, Department of Immunology, MS#351, 332 N Lauderdale, Memphis, TN 38105, USA.
- Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
- These authors contributed equally to this work.
Correspondence to: Douglas R. Green1,2,4 e-mail: douglas.green@stjude.org
Correspondence to: Helen M. Beere1,2,4 e-mail: helen.beere@stjude.org
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