The Antisocial Network: Cross Talk Between Cell Death Programs in Host Defense

Abstract

Nearly all animal cells contain proteins evolved to trigger the destruction of the cell in which they reside. The activation of these proteins occurs via sequential programs, and much effort has been expended in delineating the molecular mechanisms underlying the resulting processes of programmed cell death (PCD). These efforts have led to the definition of apoptosis as a form of nonimmunogenic PCD that is required for normal development and tissue homeostasis, and of pyroptosis and necroptosis as forms of PCD initiated by pathogen infection that are associated with inflammation and immune activation. While this paradigm has served the field well, numerous recent studies have highlighted cross talk between these programs, challenging the idea that apoptosis, pyroptosis, and necroptosis are linear pathways with defined immunological outputs. Here, we discuss the emerging idea of cell death as a signaling network, considering connections between cell death pathways both as we observe them now and in their evolutionary origins. We also discuss the engagement and subversion of cell death pathways by pathogens, as well as the key immunological outcomes of these processes.

Keywords: apoptosis; cell death; host; necroptosis; pathogen; pyroptosis.

Figure 1

Programmed cell death pathways function as interconnected signaling networks that coordinate host defense. Stress- or infection-associated stimuli are detected through a repertoire of innate immune receptors, resulting in the concomitant or sequential activation of cell death signaling programs. Apoptotic, necroptotic, and pyroptotic signaling contribute various immunological outputs, including entry of cell- or pathogen-associated antigens into presentation pathways, the removal of a replicative niche for intracellular pathogens, de novo production of inflammatory cytokines and chemokines, and release of DAMPs. The composition of these outputs tailors the generation of an immune response mounted in response to programmed cell death. Abbreviations: DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern.

Figure 2

Overview of programmed cell death signaling pathways. (a) Apoptosis occurs following extrinsic activation of death receptor family members or intrinsic perturbation of mitochondrial membrane dynamics. Extrinsic apoptosis requires the formation of proapoptotic CASP8 homodimers paired with suppression of the inhibitory FADD/CASP8/cFLIP complex, while intrinsic apoptosis results in CASP9 activation downstream of MOMP triggered by cellular stresses that skew the ratio of proapoptotic Bcl-2 family members. Both CASP8 and CASP9 activate the executioner caspases CASP3 and CASP7, which cleave cellular substrates to induce apoptotic cell death characterized by membrane blebbing and the expression of eat-me signals on apoptotic bodies including phosphatidylserine and calreticulin. (b) Necroptosis occurs upon activation of death receptors, certain TLRs, or ZBP1. When paired with suppression of the aforementioned inhibitory FADD/CASP8/cFLIP complex, these signals trigger either RIPK1-dependent or RIPK1-independent assembly and phosphorylation of RIPK3 oligomers. Activated RIPK3 then mediates two separate signaling outcomes: phosphorylation and activation of the necroptosis executioner MLKL, which forms pores in cellular membranes, and activation of transcription factors such as NF-κB and IRF1 that mediate inflammatory gene expression. This leads to lytic cell death that releases cell-associated antigens and DAMPs, paired with de novo cytokine and chemokine production. (c) Pyroptosis is engaged following the detection of PAMPs or pathogen-associated cellular stressors by cytosolic sensors such as NLRP3, NLRC4, or AIM2, which recruit pro-CASP1 and form a multimeric signaling complex termed the inflammasome. Inflammasome assembly results in activation of CASP1, which carries out two effector functions: the cleavage and activation of the pyroptosis executioner GSDM-D, which forms pores in the plasma membrane, and the processing and activation of IL-1 family cytokines. CASP1 activation therefore results in the secretion of IL-1 cytokines through GSDM pores and eventual cell lysis due to imbalanced osmolarity. Abbreviations: cFLIP, cellular FLICE-inhibitory protein; CRT, calreticulin; cytoC, cytochrome c; FADD, Fas-associated death domain; DAMP, damage-associated molecular pattern; dsDNA, double-stranded DNA; GSDM, gasdermin; LPS, lipopolysaccharide; MOMP, mitochondrial outer membrane permeabilization; PAMP, pathogen-associated molecular pattern; PS, phosphatidylserine; ROS, reactive oxygen species; SMAC, second mitochondria-derived activator of caspases; tBID, truncated BID; TLR, Toll-like receptor; XIAP, X-linked inhibitor of apoptosis.

Figure 3

Network interactions between cell death pathways lead to hybrid forms of programmed cell death. (a) Apoptotic and necroptotic signaling machinery are tightly connected, as extrinsic death receptor signaling through the RIPK1/FADD/CASP8 complex can lead to pleiotropic signaling outcomes. In the absence of RIPK or caspase inhibition, prosurvival programs through NF-κB dominate; if RIP kinases are inhibited, extrinsic apoptosis via CASP8 homodimerization occurs; if caspases are inhibited; necroptosis is enabled through RIPK1-RIPK3 oligomerization. (b) Necroptotic signaling interfaces with pyroptosis through the executioner MLKL. RIPK3 oligomerization downstream of extrinsic DR ligation or cytosolic ZBP1 activation leads to the phosphorylation of the executioner molecule MLKL, which forms pores in cellular membranes including the plasma membrane. MLKL-mediated K⁺ efflux can subsequently trigger NLRP3 activation, leading to inflammasome assembly and CASP1 cleavage that mediates GSDM-D pore formation and the processing of IL-1 family cytokines. (c) Expanded substrate targeting by caspases connects apoptotic and pyroptotic signaling components. Inflammasome engagement leads to CASP1 activation, which in addition to cleaving its canonical substrates of GSDM-D and IL-1 family cytokine precursors can mediate the activation proteolysis of BID into proapoptotic tBID, triggering MOMP and apoptosome formation. CASP1 can also directly cleave CASP11 to promote inflammatory pyroptotic signaling, through poorly understood mechanisms. Additionally, the apoptotic executioner CASP3 can target the pyroptotic executioner GSDM-E for proteolysis, leading to gasdermin pore formation and morphological aspects of pyroptosis. Abbreviations: cFLIP, cellular FLICE-inhibitory protein; DAMP, damage-associated molecular pattern; FADD, Fas-associated death domain; GSDM, gasdermin; MOMP, mitochondrial outer membrane permeabilization; tBID, truncated BID.