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Emerging connectivity of programmed cell death pathways and its physiological implications

Abstract

The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.

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Fig. 1: Different forms of programmed cell death lead to different bystander responses.
Fig. 2: Molecular mechanisms of apoptosis pathway activation.
Fig. 3: Molecular features of inflammasome activation and pyroptosis.
Fig. 4: Induction of necroptosis.
Fig. 5: The role of cell death in host responses to infection.
Fig. 6: The molecular mechanisms of cell survival regulation by TNFR1 signalling.
Fig. 7: Overlap and backup of apoptosis and pyroptosis as means to induce cell death.

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Acknowledgements

We are grateful to the present and past members of our laboratories, our collaborators and the mentors that we have had the pleasure of working with. Our work is supported by grants and fellowships from the Australian National Health and Medical Research Council (Project Grants 1186575 and 1145728 to M.J.H., 1143105 to M.J.H. and A.S., 1159658 to M.J.H. and S.B., Program Grant 1016701 to A.S., and Fellowships 1020363, to A.S., and 1156095, to M.J.H.), by the Leukemia and Lymphoma Society of America (grant LLS SCOR 7001-13 to A.S. and M.J.H.), by the Cancer Council of Victoria (project grants 1147328, to M.J.H., and 1052309, to A.S.) and by a Venture Grant to M.J.H. and A.S.

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Glossary

BCL-2 (B cell leukaemia/lymphoma-2) family

A family of proteins — named after its original member, BCL-2 — that regulate the intrinsic apoptotic pathway.

Complement system

Evolutionarily ancient system of protein cascades capable of lysing bacteria by perforating their outer membrane, opsonizing the pathogens and activating the cells of the immune system.

Damage-associated molecular patterns

(DAMPs, also known as alarmins). Intracellular molecules, such as HMGB1 or S100A8, whose release from cells undergoing lytic cell death triggers distinct receptors in innate immune cells and causes inflammation.

Pathogen-associated molecular patterns

(PAMPs). Evolutionarily conserved molecular components of pathogens, such as LPS expressed by Gram-negative bacteria, that cause inflammatory responses by innate immune cells.

Pattern recognition receptors

Membrane-associated or cytosolic receptors capable of recognizing and responding to PAMPs through the induction of pro-inflammatory responses.

TAM receptors

Family of receptor tyrosine kinases (TYRO3, AXL, MERTK) that promote apoptotic cell clearance by binding to phosphatidylserine exposed on apoptotic cells using GAS6 and protein S as bridging ligands.

BH3-only proteins

Pro-apoptotic members of the BCL-2 protein family that share only one of the four BCL-2 homology (BH) domains, namely the BH3 domain, with the remainder of the family. BH3-only proteins are induced transcriptionally and/or activated post-translationally in response to developmental cues or cytotoxic stimuli that initiate the intrinsic apoptotic cell death pathway.

Mitochondrial outer membrane permeabilization

(MOMP). Perforation of the outer mitochondrial membrane, causing leakage of content from the mitochondrial intermembrane space, including the apoptosis inducers cytochrome c and SMAC. MOMP can result in the translocation of mitochondrial DNA into the cytosol, leading to the production of type I interferons and thereby driving inflammatory responses.

Inhibitor of apoptosis proteins

(IAPs). Family of proteins with structural homology (that is, baculovirus IAP repeats). Some of the IAP proteins have an E3 ubiquitin ligase function, allowing them to ubiquitylate their target proteins. XIAP inhibits apoptosis by binding to and promoting the degradation of caspases 3 and 7, whereas cIAP1 and cIAP2 promote pro-survival signalling from TNFR1 by enhancing NF-κB activation.

Death receptors

Subsets of the TNFR superfamily that contain an intracellular death domain, which upon ligation can induce killing of the cells on which they are expressed through FADD adaptor protein-mediated activation of caspase 8.

cFLIP

(cellular CASP8 and FADD-like apoptosis regulator). Protein with structural similarity to caspase 8 but that lacks enzymatic activity. There are two forms of FLIP: FLIP short and FLIP long. FLIP short inhibits apoptosis by preventing the activation of caspase 8; FLIP long can form heterodimers with caspase 8, and this heterodimer inhibits necroptosis by cleaving RIPK1. High levels of FLIP long can also inhibit caspase 8 activation and apoptosis.

Inflammasomes

Multimeric protein complexes, activated by various events, including ion flux, reactive oxygen species and mitochondrial dysfunction. They comprise sensors, such as NLR molecules, and their formation often depends on the adaptor protein ASC and pro-caspase 1, which together cause the autocatalytic activation of caspase 1. The consequent proteolytic processing of pro-IL-1β and pro-IL-18 into their bioactive forms results in inflammation and proteolytic activation of gasdermin D to drive pyroptotic cell death.

NLR (nucleotide-binding domain and leucine-rich repeat containing) family

Evolutionarily conserved diverse family of proteins, further classified into NLRA, NLRB, NLRP and NLRC, in accordance with their N-terminal domains and the presence or absence of CARD domains. Certain (but probably not all) NLRs function in innate immune sensing of pathogens and infection-associated cellular changes. They contribute to the protection of the infected host by instructing an antimicrobial defence, including inflammatory responses.

Type III secretion (T3SS) apparatus

Complex molecular machines used by bacteria to inject effector proteins into eukaryotic host cells.

Flagellin

Subunit protein of the flagellum that endows bacteria with motility.

Gasdermin family

Conserved family of proteins in vertebrates, named after the restriction of gasdermin A to gut and skin epithelial cells, although it is now clear that these proteins are much more widely expressed. At least some of the gasdermins can form pores in membranes after proteolytic cleavage (for example, through processing of gasdermin D by caspase 1 or 11).

ESCRT

(endosomal sorting complexes required for transport). Multiprotein machinery that enables membrane bending/budding away from the cytoplasm.

Lipopolysaccharide

(LPS). Large molecules, comprising a lipid and a complex polysaccharide, found in the outer membrane of Gram-negative bacteria.

Gram-negative bacteria

Diverse group of bacteria defined by their inability to retain crystal violet (or Gram) stains, because of the architecture of their cell envelope being composed of an inner cytoplasmic and outer bacterial cell membrane separated by a thin peptidoglycan cell wall. Typical examples include Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, Chlamydia trachomatis and Yersinia pestis.

Toll-like receptor

Family of transmembrane receptors that recognize PAMPs and DAMPs and, upon stimulation, can induce diverse pro-inflammatory responses.

RIG-I-like receptors

Cytosolic pattern recognition receptors that respond to double-stranded RNA.

Antigen-presenting cells

While all nucleated cells can present antigens, the group of professional antigen-presenting cells, which comprise macrophages, dendritic cells and B cells, are capable of priming naive T cells by the processing and presentation of antigen-derived peptides in the context of class I or class II MHC molecules and by the delivery of co-stimulatory signals.

PB1-F2

A protein encoded by the influenza A virus that contributes to its pathogenicity.

M2 protein

Protein encoded by the influenza A virus that is part of the viral envelope; it is capable of forming a tunnel between host cell compartments.

Z-RNAs

Left-handed form of double-stranded RNA that is bound by proteins, such as ADAR, ZBP1 or their viral homologues.

Cytotoxic lymphocytes

CD8+ T cells and natural killer cells, which can kill infected or malignant cells via diverse mechanisms, including the delivery of perforin and granzymes, the use of FAS ligand to activate the death receptor FAS, and the delivery of IFNγ to target cells.

BH3-mimetic drugs

Small-molecule inhibitors of pro-survival BCL-2 proteins. They mimic the action of the pro-apoptotic BH3-only proteins, which as the natural cellular inhibitors of pro-survival BCL-2 proteins are critical for the initiation of the intrinsic apoptosis signalling pathway.

Necrosome

Protein complex consisting of RIPK1, RIPK3 and FADD. This complex is formed in response to TNFR1 stimulation when both the activation of NF-κB and caspase 8 activity are blocked. This signalling complex causes the activation of the pseudokinase MLKL, the critical effector of necroptosis.

Tumour lysis syndrome

Caused by the failure to safely remove large numbers of dying tumour cells during anticancer therapy, which can cause renal failure, cardiac abnormalities, seizures and sudden death.

CAR (chimeric antigen receptor) T cells

T lymphocytes engineered to express artificial antigen receptors capable of directly recognizing proteins on cancer cells and killing these malignant cells.

Amyloid plaques

Beta-amyloid protein aggregates implicated in the destruction of nerve connections, thus causing degenerative disorders, such as Alzheimer disease.

Periodic fever syndrome

Group of rare genetic autoinflammatory diseases in which patients develop periodic fevers with a range of inflammatory pathologies, including stomatitis, aphtitis and adenitis.

Serpin

Superfamily of proteins that share a structural homology, where many perform serine protease inhibitory activity whereas others (for example, CrmA from cowpox virus) perform cysteine protease inhibitory activity.

Canonical and non-canonical NF-κB pathways

Induced by the stimulation of a variety of surface receptors (for example, TLRs, members of the TNFR superfamily, and antigen receptors), the two distinct NF-κB signalling pathways involve different members of the NF-κB/REL protein family. The classical/canonical NF-κB pathway operates via heterodimers of NF-κB1 (its cleavage product p50) with RELA or c-REL, whereas the non-canonical pathway is mediated mainly by heterodimers of NF-κB2 (its cleavage product p52) with RELB.

cGAS

Intracellular DNA sensor that induces an interferon response.

Mast cells

Tissue-resident cells involved in immune defence against parasitic infections and allergic responses.

Ripoptosomes

Signalling platforms comprising RIPK1, RIPK3, FADD and caspase 8 that can induce either apoptosis or necroptosis, depending on the state of the cell.

Immune checkpoint signalling

Signalling pathways that attenuate the activity of immune cells, mainly T lymphocytes, thereby regulating immune responses and preventing the destruction of self-tissues (contributing to self-tolerance). The inhibition of immune checkpoint regulators, such as PD1 or CTLA4, can enhance CD8+ cytotoxic T cell-mediated killing of cancer cells.

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Bedoui, S., Herold, M.J. & Strasser, A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol 21, 678–695 (2020). https://doi.org/10.1038/s41580-020-0270-8

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