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Two mechanisms of caspase 9 processing in double-stranded RNA- and virus-triggered apoptosis

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Abstract

Viral double-stranded RNA (dsRNA) is a ubiquitous intracellular “alert signal” used by cells to detect viral infection and to mount anti-viral responses. DsRNA triggers a rapid (complete within 2–4 h) apoptosis in the highly-susceptible HeLa cell line. Here, we demonstrate that the apical event in this apoptotic cascade is the activation of procaspase 8. Downstream of caspase 8, the apoptotic signaling cascade bifurcates into a mitochondria-independent caspase 8/caspase 3 arm and a mitochondria-dependent, caspase 8/Bid/Bax/Bak/cytochrome c arm. Both arms impinge upon, and activate, procaspase 9 via two different cleavage sites within the procaspase 9 molecule (D330 and D315, respectively). This is the first in vivo demonstration that the “effector” caspase 3 plays an “initiator” role in the regulation of caspase 9. The dsRNA-induced apoptosis is potentiated by the inhibition of protein synthesis, whose role is to accelerate the execution of all apoptosis steps downstream of, and including, the activation of caspase 8. Thus, efficient apoptosis in response to viral dsRNA results from the co-operation of the two major apical caspases (8 and 9) and the dsRNA-activated protein kinase R (PKR)/ribonuclease L (RNase L) system that is essential for the inhibition of protein synthesis in response to viral infection.

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon, 97239

    M. S. Iordanov, O. P. Ryabinina & B. E. Magun

  2. Department of Biochemistry, University of Lausanne, CH-1066, Epalinges, Switzerland

    P. Schneider

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  1. M. S. Iordanov
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  2. O. P. Ryabinina
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  3. P. Schneider
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  4. B. E. Magun
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Correspondence to B. E. Magun.

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This work was supported by U.S. Public Health Service Grants CA-39360 and ES-08456 to B.E.M. and CA-93718 to M.S.I.

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Iordanov, M.S., Ryabinina, O.P., Schneider, P. et al. Two mechanisms of caspase 9 processing in double-stranded RNA- and virus-triggered apoptosis. Apoptosis 10, 153–166 (2005). https://doi.org/10.1007/s10495-005-6070-y

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