The Evolutionary Origins of Programmed Cell Death Signaling

Abstract

Programmed cell death (PCD) pathways are found in many phyla, ranging from developmentally programmed apoptosis in animals to cell-autonomous programmed necrosis pathways that limit the spread of biotrophic pathogens in multicellular assemblies. Prominent examples for the latter include animal necroptosis and pyroptosis, plant hypersensitive response (HR), and fungal heterokaryon incompatibility (HI) pathways. PCD pathways in the different kingdoms show fundamental differences in execution mechanism, morphology of the dying cells, and in the biological sequelae. Nevertheless, recent studies have revealed remarkable evolutionary parallels, including a striking sequence relationship between the "HeLo" domains found in the pore-forming components of necroptosis and some types of plant HR and fungal HI pathways. Other PCD execution components show cross-kingdom conservation as well, or are derived from prokaryotic ancestors. The currently available data suggest a model, wherein the primordial eukaryotic PCD pathway used proteins similar to present-day plant R-proteins and caused necrotic cell death by direct action of Toll and IL-1 receptor (TIR) and HeLo-like domains.

Figure 1.

Signaling domains and their functions in programmed cell death (PCD) pathways. This figure shows simplified versions of major PCD pathways, focusing on the interaction properties of the domains. The arrangement of the proteins in homo-oligomeric complexes is not shown. Coloring: six-helix death-fold domains (death domain [DD], death effector domain [DED], caspase activation and recruitment domain [CARD], pyrin domain [PYD]) are shown in cyan, RIP homotypic interaction motifs (RHIMs) in orange, and Toll and IL-1 receptor (TIR) domains in purple. The central STAND ATPase domains (both NB-ARC and NACHT type) are blue and repetitive sensor domains (leucine-rich repeat [LRR], WD40) are green. Caspase domains are yellow and supposedly pore-forming domains (gasdermin amino-terminal domain, HET domain, and HeLo/coiled-coil [CC]) are shown in red. All other domain types are shown in gray. Homotypic oligomerization is indicated by double arrows colored by domain type. Proteolytic cleavage is indicated by a scissors symbol, whereas translocation events are shown as red arrows. Cell death stimuli are shown on a black background. (A) Apoptosis. Both the extrinsic pathway, triggered by ligand binding to a death receptor, and the intrinsic pathway initiated by a mitochondrial signal are shown. (B) Necroptosis. Only the main components of the canonical pathway, triggered by TNF-receptor type 1 (TNFR1) ligation, is shown here. (C) Pyroptosis. Both major pathways are shown: caspase-11 (human: caspase-4/5) triggering by intracellular lipopolysaccharide (LPS), and caspase-1 activation by signalosome signaling. (D) Fungal heterokaryon incompatibility (HI). Two HI systems are shown: Het-E (from one fusion partner) being triggered by Het-C (contributed by the other partner), and Het-S (from one fusion partner) being recruited to an amyloid formed by Het-s (from the other fusion partner). (E) Plant hypersensitive response. One example for each class of R-protein is shown: The CC-NB-LRR (CNL)-based ZAR1 resistosome is triggered by the ZAR1/RKS1 complex recognizing PBL2, which has been previously modified by the pathogen effector AvrAC. The dimer of the two TIR-NB-LRR (TNL)-based STAND proteins RPS4 and RRS1 is triggered by binding to the pathogen effector AvrRps4 and signals cell death via the EDS1/SAG101 complex.

Figure 2.

Evolutionary origins of cell death protein architectures. This figure shows generic protein architectures found in metazoans, fungi, and plants—and what is predicted to have existed in an ancestral (early eukaryote) organism. Domain coloring identical to Figure 1. The ancestral system is predicted to mainly have used STAND ATPases, most likely of the NB-ARC type, with amino-terminal Toll and IL-1 receptor (TIR) and HeLo-like domains. However, NACHT-ATPases and a mixed-lineage kinase domain-like (MLKL) HeLo-domain kinase might also have been present. In the plant lineage, components of EDS1 and probably many other relevant proteins have been acquired. The coiled-coil [CC]-domain found in present plant CC-NB-LRR (CNL) proteins was either acquired or, more likely, evolved from the HeLo domain. RIP homotypic interaction motifs (RHIMs) are first seen in the opisthokont lineage, whereas the six-helix death-fold domains are specific for the metazoan lineage. A more detailed description of early cell death evolution is given in the main text.