PANoptosis

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PANoptosis is a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through multiprotein PANoptosome complexes. [1] [2] The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer. [1] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRC5- and NLRP12-PANoptosomes, have been characterized so far. [1] [17] [18] [19] [20] [21] [22] [23]

Contents

Emerging genetic, molecular, and biochemical studies have identified extensive crosstalk among the molecular components across various cell death pathways in response to a variety of pathogens and innate immune triggers. [3] [4] Historically, inflammatory caspase-mediated pyroptosis  and RIPK-driven necroptosis were described as two major inflammatory cell death pathways. While the PANoptosis pathway has some molecular components in common with pyroptosis and necroptosis, as well as with the non-lytic apoptosis pathway, these mechanisms are separate processes that are associated with distinct triggers, protein complexes, and execution pathways. [2] Inflammasome-dependent pyroptosis involves inflammatory caspases, including caspase-1 and caspase-11 in mice, and caspases-1, -4, and - 5 in humans, and is executed by gasdermin D. [24] [25] [26] [27] [28] [29] [30] In contrast, necroptosis occurs via RIPK1/3-mediated MLKL activation, which is downstream of caspase-8 inhibition. [31] [32] [33] [34] On the other hand, PANoptosis is [TDK1] driven by caspases and RIPKs and is executed by gasdermins, MLKL, NINJ1, and potentially other yet to be identified molecules cleaved by caspases. [35] [36] [37] [38] [39] [40] [19] [21] Moreover, caspase-8 is essential for cell death in PANoptosis [41] [42] but needs to be inactivated or inhibited to induce necroptosis. [43] [44]

Summary of the different morphologies, mechanisms and outcomes of apoptosis, pyroptosis, necroptosis, and PANoptosis

CharacteristicsApoptosisPyroptosisNecroptosisPANoptosis
MorphologyCell lysisNoYesYesYes
Pore formationNoYesYesYes
MechanismCaspase activationYesYesNoYes
Gasdermin activationNoYesNoYes
RIPK1YesNoYesYes
RIPK3NoNoYesYes
OutcomeIL-1b and IL-18 releaseNoYesNoPossible
DAMP releaseNoYesYesYes
InflammationNoYesYesYes
Programmed cell deathYesYesYesYes

Clinical Relevance

PANoptosis has also been implicated in inflammatory diseases, neurological diseases, and cancer. Additionally, activation of PANoptosis can clear infected cells for host defense, and it has shown preclinical promise as an anti-cancer strategy. [45] [46] [47] [48] [49] [50] [51] [52] [53] [54]

Viral Infections

PANoptosis has now been identified in a variety of infections, incluiding influenza A virus, herpes simplex virus 1 (HSV1), and coronavirus. For example, PANoptosis is important for host defense during influenza infection through the ZBP1-PANoptosome and during HSV1 infections through the AIM2-PANoptosome. Studies with beta-coronaviruses have shown that IFN can induce ZBP1-mediated PANoptosis during SARS-CoV-2 infection, thereby limiting the efficacy of IFN treatment during infection and resulting in morbidity and mortality. This suggests that inhibiting ZBP1 may improve the therapeutic efficacy of IFN therapy during SARS-CoV-2 infection and possibly other inflammatory conditions where IFN-mediated cell death and pathology occur. [55] [56]

Bacterial Infections

In Yersinia pseudotuberculosis infections, PANoptosis is induced through the RIPK1-PANoptosome, and the deletion of caspase-8 and RIPK3 prevents cell death. During Francisella novicida infection, PANoptosis occurs through the AIM2-PANoptosome. [5] [7] [17] [19] PANoptosis has also been observed in Salmonella enterica and Listeria monocytogenes infections, where the combined loss of caspases and RIPK3 significantly protects cells from death. [57]

Fungal Infections

PANoptosis also occurs in fungal infections, including those caused by Candida albicans and Aspergillus fumigatus . [58]

Cancer

Treatment of cancer cells with the PANoptosis-inducing agents TNF and IFN-γ [59] [6]  can reduce tumor size in preclinical models. [60] The combination of the nuclear export inhibitor selinexor and IFN can also cause PANoptosis and regress tumors in preclinical models. [3] [61]

Hematologic disorders

More recent evidence suggests that NLRC5- NLRP12-mediated PANoptosis is activated by heme, which can be released by red blood cell lysis during infection or inflammatory disease, in combination with specific components of infection or cellular damage. Deletion of NLRP12 protects against pathology in animal models of hemolytic disease, suggesting this could also act as a therapeutic target. Similarly, the NLRC5-PANoptosome, which also contains NLRP12, was identified as a response to NAD+ depletion downstream of heme-containing triggers. Deletion of NLRC5 protects against not only hemolytic disease models, but also colitis and HLH models. [22] [23]

Fever

Additionally, PANoptosis can be induced by heat stress (HS), such as fever, during infection, and NINJ1 is a key executioner in this context. Deletion of NINJ1 in a murine model of HS and infection reduces mortality; furthermore, deleting essential PANoptosis effectors upstream completely rescues the mice from mortality, thereby identifying NINJ1 and PANoptosis effectors as potential therapeutic targets. [62]

Therapeutic Potential

The regulation of PANoptosis involves numerous PANoptosomes, which include multiple sensor molecules such as NLRP3, ZBP1, AIM2, NLRC5, and NLRP12, along with complex-forming molecules such as caspases and RIPKs. These components activate various downstream cell death executioners and play a role in disease. Therefore, modulating the components of this pathway has potential for therapy. However, excessive activation of PANoptosis can lead to inflammation, inflammatory disease, and cytokine storm syndromes. [6] [11] [63] [21] [1] Treatments that block TNF and IFN-γ to prevent PANoptosis have provided therapeutic benefit in preclinical models of cytokine storm syndromes, including cytokine shock, SARS-CoV-2 infection, sepsis, and hemophagocytic lymphohistiocytosis, suggesting the therapeutic potential of modulating this pathway. [6] [64]

Related Research Articles

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Cell death</span> Biological cell ceasing to carry out its functions

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as diseases, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Caspase 1</span> Enzyme found in humans

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">RIPK1</span> Enzyme found in humans

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis, necroptosis, and PANoptosis Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.

<span class="mw-page-title-main">NLRP12</span> Protein-coding gene in the species Homo sapiens

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.

<span class="mw-page-title-main">ZBP1</span> Protein-coding gene in the species Homo sapiens

Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ZBP1 gene.

<span class="mw-page-title-main">AIM2</span> Protein-coding gene in the species Homo sapiens

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">NLRC5</span> Protein-coding gene in the species Homo sapiens

NLRC5, short for NOD-like receptor family CARD domain containing 5, is an intracellular protein that plays a role in the immune system. NLRC5 is a pattern recognition receptor implicated in innate immunity to viruses potentially by regulating interferon activity. It also acts as an innate immune sensor to drive inflammatory cell death, PANoptosis. In humans, the NLRC5 protein is encoded by the NLRC5 gene. It has also been called NOD27, NOD4, and CLR16.1.

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

<span class="mw-page-title-main">GSDMD</span> Protein found in humans

Gasdermin D is a protein that in humans is encoded by the GSDMD gene on chromosome 8. It belongs to the gasdermin family which is conserved among vertebrates and comprises six members in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and DFNB59 (Pejvakin). Members of the gasdermin family are expressed in a variety of cell types including epithelial cells and immune cells. GSDMA, GSDMB, GSDMC, GSDMD and GSDME have been suggested to act as tumour suppressors.

<span class="mw-page-title-main">Thirumala-Devi Kanneganti</span> Indian immunologist

Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.

<span class="mw-page-title-main">Vishva Dixit</span> Kenyan molecular biologist

Vishva Mitra Dixit is a Kenyan-American physician who is currently Vice President and Senior Fellow of Physiological Chemistry and Research Biology at Genentech.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

Jonathan C. Kagan is an American immunologist and the Marian R. Neutra, Ph.D. Professor of Pediatrics at Harvard Medical School. He is also the director of Basic Research and Shwachman Chair in Gastroenterology at Boston Children's Hospital. Kagan is a world leader in defining the molecular basis of innate immunity and inflammation.

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