Downloaded from http://cshperspectives.cshlp.org/ on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press The Evolutionary Origins of Programmed Cell Death Signaling Kay Hofmann Institute for Genetics, University of Cologne, Cologne D-50674, Germany Correspondence: [email protected] Programmed cell death (PCD) pathways are found in many phyla, ranging from developmen- tally 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 king- doms show fundamental differences in execution mechanism, morphology of the dying cells, and in the biological sequelae. Nevertheless, recent studies have revealed remarkable evo- lutionary 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. rogrammed cell death (PCD), either initiated nisms are beginning to be unraveled. At first Pcell autonomously in response to pathogens glance, PCD pathways in different kingdoms or stimulated from the outside through signaling appear to work by fundamentally different molecules, is of crucial importance for the suc- rules, although a number of recent studies have cess of multicellular organisms. Most of current revealed numerous mechanistic parallels and in- cell death research is focused on animals and stances of clear evolutionary interkingdom rela- plants, with mammals taking center stage, tionships of cell death mediators. These findings whereas substantial work is also devoted to mod- suggest that at least a core pathway for PCD has el metazoans such as Drosophila melanogaster existed in the common ancestor of metazoans, and Caenorhabditis elegans,ortoArabidopsis fungi, and plants. The following paragraphs will thaliana as the main model for plant cell death provide a synopsis of major cell death pathways pathways. However, cell death pathways have in different kingdoms and will highlight the evo- also been described in other organisms such as lutionary processes leading to the diversification filamentous fungi, and their molecular mecha- of PCD pathways observed today. Editors: Kim Newton, James M. Murphy, and Edward A. Miao Additional Perspectives on Cell Survival and Cell Death available at www.cshperspectives.org Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a036442 Cite this article as Cold Spring Harb Perspect Biol 2020;12:a036442 1 Downloaded from http://cshperspectives.cshlp.org/ on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press K. Hofmann PROGRAMMED CELL DEATH SYSTEMS IN sis,” because the dying cells look morphological- DIFFERENT KINGDOMS ly different and the signaling cascades and death effectors appear—at least at first glance—unre- PCD modalities can be classified as “necrotic” lated to their metazoan counterparts. In the (i.e., accompanied by membrane rupture and absence of circulating phagocytic cells, a perma- release of intracellular material), and “non- nent containment characteristic of metazoan necrotic” without such leakage (Ashkenazi apoptosis is unlikely; whether this containment and Salvesen 2014). Because metazoan apopto- is important in the absence of an inflammatory sis is the major—if not the only—example for system is not clear. There is at least one class the latter type, non-necrotic cell death is usually of PCD pathway in plants called the “hypersen- referred to as “apoptotic.” As compared with sitive response” (HR), which has been shown apoptosis, necrotic cell death is less intricate to be associated with DAMP release, therein and far more widespread. Because cell death resembling metazoan programmed necrosis caused by major mechanical, chemical, or bio- pathways (Morel and Dangl 1997; Balint-Kurti logical insults is typically associated with cell 2019). The HR is a part of the so-called “effector rupture, necrosis was initially considered to triggered immunity” (ETI) system, which gets be a hallmark of non-PCD and it took a long activated on the detection of pathogen-derived time until “programmed necrosis” was accepted proteins within the host cell. The HR cell death as a reality (Edinger and Thompson 2004). is called “hypersensitive” because it exceeds In animals, several different types of pro- the damage directly inflicted by the pathogen; grammed necrosis exist, among which necro- its function is to limit the spread of biotrophic ptosis and pyroptosis are the best understood pathogens. The production and release of and probably most important examples (Cook- DAMPs—among them the small molecule sali- son and Brennan 2001; Bergsbaken et al. 2009; cylic acid (SA)—serves the purpose to alert other Vandenabeele et al. 2010). Cells dying by parts of the plants of the ongoing infection (Ba- programmed necrosis release intracellular lint-Kurti 2019). contents, several components of which are in- Outside of animals and plants, PCD path- terpreted as “damage-associated molecular ways exist (Ameisen 2002), but only a few of patterns” (DAMPs) by the immune system, re- them have been characterized in molecular sulting in inflammation (Schaefer 2014; Roh detail. Filamentous fungi belonging to the Asco- and Sohn 2018). Apoptosis, in contrast, is a mycetes possess a number of functionally more complicated process because it has to re- analogous, but molecularly diverse cell death liably kill the cell while at the same time pre- pathways required for a process called “hetero- venting the leakage of intracellular material karyon incompatibility” (HI) (Saupe 2000; Das- and DAMPs. This is no easy task, considering kalovet al. 2017). Filamentous ascomycetes grow that cellular compartments such as the lyso- an extensive network of hyphae, which can both some and the mitochondrion contain enzymes branch off and merge back—provided that the and oxidants with the potential to damage cell merging hyphae are genetically identical. Multi- membranes. During apoptosis, the cell is bro- ple HI systems prevent the successful fusion of ken into a number of smaller, membrane- hyphae emanating from genetically different in- enclosed vesicles called “apoptotic bodies,” dividuals, thereby safeguarding against the which are subsequently removed by phagocytic spread of pathogens (Daskalov et al. 2017). For processes (Elmore 2007; Nagata 2018). Apopto- a successful hyphal fusion, each of the available sis is therefore ideally suited for develop- HI systems has to be “disarmed” separately— mentally scheduled cell death, a physiological usually by the two fusion partners being homo- process not supposed to alert the immune sys- zygous atapolymorphic sensor locus.Triggering tem (Fuchs and Steller 2011). only one of the HI systems is sufficient to cause Nonmetazoan forms of PCD are not easily localized cell death near the point of fusion. The classified as “apoptosis” or “programmed necro- formation of intrahyphal septa prevents the 2 Cite this article as Cold Spring Harb Perspect Biol 2020;12:a036442 Downloaded from http://cshperspectives.cshlp.org/ on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Evolution of Cell Death spreading of the cell death over the entire hyphal imal caspase-9 molecules can cleave and thereby system. For several fungal species, in particular activate each other. There are several pathways for the HI model organism Podospora anserina, leading to apoptosome activation, either cell au- multiple HI systems and their sensor proteins tonomously or responding to external stimuli have been described (Saupe 2000; Daskalov via death receptors (Elmore 2007). These up- et al. 2017; Gonçalves et al. 2017). stream pathways use other caspases (caspase-8, caspase-10) and other hetero-oligomerization domains, such as the “death domain” (DD) MOLECULAR FEATURES OF PROGRAMMED and the “death effector domain” (DED), which DEATH PATHWAYS connect the apoptotic signaling components This section provides a synopsis of major PCD and can lead to the activation of caspases via pathways, which are mechanistically under- induced oligomerization and cleavage. stood to some degree. In particular, the molec- ular architecture of the key components is sum- Necroptosis marized, as this information is necessary to appreciate the evolutionary ancestry of PCD A simplified version of the core necroptosis pathways. pathway is shown in Figure 1B, and more de- tailed descriptions can be found in Newton and Manning (2016), Weinlich et al. (2017), and Apoptosis Petrie et al. (2019). The key step committing a A simplified version of the apoptosis pathway is cell to necroptosis is the oligomerization and shown in Figure 1A, and detailed reviews can be activation of the protein kinase RIPK3. RIPK3 found in Elmore (2007) and Nagata (2018). The possesses a central RHIM (RIP homotypic crucial step in apoptotic cell death induction is interaction motif), which is important for re- the activation