No death without life: vital functions of apoptotic effectors

We found that CED-4 translocates to the nuclei of germline cells upon exposure of nematodes to ionizing irradiation, in an ATM- and

L Galluzzi


Scholarcy highlights

  • (and named ced genes, for ‘C. elegans death’), yet had no discernible function in its ordinary life. The concept was born that the apoptotic machinery of C. elegans, as built up by CED-3, CED-4, CED-9 and EGL-1, would solely exist for the regulation and execution of cell death, and would have no important roles in normal life
  • Omi stress-regulated endoprotease/high temperature requirement protein A 2 indirectly favors the activation of caspases by sequestering and cleaving inhibitor of apoptosis proteins, and contributes to the execution of apoptosis via the cleavage of caspase-unrelated substrates like cytoskeletal proteins
  • Two independent lines of evidence indicate that the cell cycle-modulatory effect of CED-4 does not require the activation of apoptotic effectors: the absence of CED-4 continues to reduce the DNA damage-induced cell-cycle arrest when the absence of proapoptotic proteins such as EGL-1 or CEP-1 does not influence the cell cycle; and loss-of-function mutations in ced-4 affects the cell cycle in a genetic background where CED-3 cannot be activated and caspase-dependent apoptosis does not occur
  • The results outlined above suggest that cell death regulators have vital functions that are phylogenetically conserved. Formal proof for this concept is lacking, it appears plausible that the cell deathunrelated function of such proteins is the most ancestral one and that the lethal function has been acquired later during evolution. It seems that apoptosis effectors exhibit vital functions that are prominently involved in the adaptation to stress such as redox stress, metabolic stress, DNA damage) or thermotolerance
  • This applies to caspases, which play a role in inflammation and immunity, the host responses to pathogen invasion-induced stress
  • It is tempting to speculate that proteins involved in stress adaptation of individual cells might become potential death effectors later during evolution

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