Just So Stories about the Evolution of Apoptosis

Abstract

Apoptosis is a form of active cell death engaged by developmental cues as well as many different cellular stresses in which the dying cell essentially 'packages' itself for removal. The process of apoptotic cell death, as defined at the molecular level, is unique to the Metazoa (animals). Yet active cell death exists in non-animal organisms, and in some cases molecules involved in such death show some sequence similarities to those involved in apoptosis, leading to extensive speculation regarding the evolution of apoptosis. Here, we examine such speculation from the perspective of the functional properties of molecules of the mitochondrial apoptotic cell death pathway. We suggest scenarios for the evolution of one pathway of apoptosis, the mitochondrial pathway, and consider how they might be tested. We conclude with a 'Just So Story' of how the mitochondrial pathway of apoptosis might have evolved during eukaryotic evolution.

Figure 1. Variations on a theme: the mitochondrial pathway of apoptosis

(A) In chordates, echinoderms, platyhelminths, and possibly other phyla, apoptotic conditions engage the members of the Bcl-2 family, which either promote (green) or inhibit (red) MOMP in response to activation of BH3-only proteins. MOMP results in the release of cytochrome c (cyt c) and other proteins of the intermembrane space. Cytochrome c binds to APAF1, which oligomerizes to create the apoptosome that in turn binds to and activates an initiator caspase. The initiator caspase cleaves and thereby activates executioner caspases. Both the initiator and executioner caspases are inhibited by an inhibitor of apoptosis protein (IAP). MOMP releases antagonists of the IAP (IAPi), permitting the executioner caspases to orchestrate apoptosis. Asterisks (*) refer to active caspases. (B) In nematodes, the anti-apoptotic Bcl-2 protein sequesters the APAF1 homolog. Apoptotic conditions induce expression of BH3-only proteins, which bind to the Bcl-2 protein, releasing the APAF1 homolog to form an apoptosome. This binds and thereby activates the caspase to promote apoptosis. (C) In Drosophila, the APAF1 homolog appears to spontaneously form an apoptosome, but the initiator caspase is inhibited by an IAP. Apoptotic conditions promote expression of IAPi, permitting the apoptosome to now activate the initiator caspase, which in turn cleaves and thereby activates executioner caspases, promoting apoptosis. Note that MOMP, upstream of caspase activation, occurs only in the pathway shown in (A).

Figure 2. Variations on a theme: caspase activation platforms

(A) Some caspases (caspase-4, caspase-5, caspase-11) bind directly to intracellular lipopolysaccharides (LPS), causing caspase dimerization and, hence, activation. (B) An example of an inflammasome is shown. NLRP3 is activated to oligomerize under conditions, for example, in response to a decrease in intracellular K⁺ concentrations. NLRP3 binds to an adaptor protein, which in turn binds to caspase-1, resulting in its activation. (C) The activation of APAF1 by cytochrome c, as described in Figure 1A. Asterisks (*) refer to active caspases.