ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis)

Malireddi, R. K. Subbarao; Kesavardhana, Sannula; Kanneganti, Thirumala‐Devi

doi:10.3389/fcimb.2019.00406

Cited by 304 publications

(239 citation statements)

References 98 publications

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“…The unveiling of ZBP1 and TAK1 as master regulators of pyroptosis, apoptosis, and necroptosis, along with the rapidly expanding evidence of communication between these pathways, has led to the concept of PANoptosis, in which a putative PANoptosome acts as a central cell death complex that can initiate all three of these pathways. 151,152 The convergence of these three programmed cell death pathways and the identification of master regulators controlling all three is intriguing and could be powerful therapeutically. Future research will be needed to determine the therapeutic potential of these master regulators and to unravel the complexities of this central PANoptotic process, including detailed exploration of the mechanisms of this multifaceted cell death.…”

Section: Activation Of Nlrp3mentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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Inflammasomes are multi-component signaling complexes critical to the initiation of pyroptotic cell death in response to invading pathogens and cellular damage. A number of innate immune receptors have been reported to serve as inflammasome sensors. Activation of these sensors leads to the proteolytic activation of caspase-1, a proinflammatory caspase responsible for the cleavage of proinflammatory cytokines interleukin-1β and interleukin-18 and the effector of pyroptotic cell death, gasdermin D. Though crucial to the innate immune response to infection, dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. Therefore, clinical interest in the modulation of inflammasome activation is swiftly growing. As such, it is imperative to develop a mechanistic understanding of the regulation of these complexes. In this review, we divide the regulation of inflammasome activation into three parts. We discuss the transcriptional regulation of inflammasome components and related proteins, the post-translational mechanisms of inflammasome activation, and advances in the understanding of the structural basis of inflammasome activation.

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Section: Activation Of Nlrp3mentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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“…Direct proteolytic cleavage of IRF3 may contribute to the reduction of type I interferon production observed in COVID19 patients [31,32]. TAB1 is part of the TAB1/2/3/TAK1 complex [70] that regulates the activity of TAK1 (TGFβ-activated kinase 1), in response to different stimuli including TGFβ, IL1, TNFα and upon viral and bacterial infection [71,72]. TAK1 can then activate the NFκB pathway or signal through the MAP kinases pathway [73,74].…”

Section: Irf3 Tab1 and Nlrp12 Are Important Components That Drive Thmentioning

confidence: 99%

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Moustaqil

Ollivier

Chiu

et al. 2020

Preprint

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The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David's Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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“…PANoptosis is a newly emerging concept that highlights the crosstalk and coordination that occurs between three of these pathways, that is, pyroptosis, apoptosis, and necroptosis. 46,47 Our team has been working on this concept for a decade to build on our initial findings that overlapping regulation occurs between the inflammasome/pyroptotic and apoptotic and necroptotic components. We first demonstrated the crosstalk between pyroptosis and apoptosis.…”

Section: Panoptosismentioning

confidence: 99%

“…IAV infection induces multiple programmed cell death pathways concomitantly, including pyroptosis, apoptosis, and necroptosis, 28 through the process of PANoptosis in murine macrophages. 46 ZBP1 is the sensor responsible for triggering PANoptosis in response to IAV 28,70,71 ( Figure 2B). In addition to IAV, ZBP1 senses flavivirus infections, like Zika virus and West Nile virus (WNV), and induces cell death-independent antiviral effects.…”

Section: Role Of Zbp1 During Virus Infectionmentioning

confidence: 99%

“…ZBP1 is the sensor for influenza virus-induced NLRP3 inflammasome activation and plays a role similar to that of caspase-11 (or caspase-4/5) in LPS-induced non-canonical NLRP3 inflammasome activation. 28,46,70 Additionally, it has key roles in the initiation of IAVinduced PANoptosis. 28,46,47,54 Even though the core complex responsible for ZBP1-NLRP3 inflammasome activation has been identified, how ZBP1 sensing of influenza virus leads to NLRP3 inflammasome activation is still not fully understood.…”

Section: Summary and Per S Pec Tive Smentioning

confidence: 99%

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The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

Zheng

Kanneganti

2020

Immunological Reviews

271

172

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ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z‐RNA produced during influenza virus infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co‐regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1‐NLRP3 inflammasome. When Z‐RNA is sensed, ZBP1 recruits RIPK3 and caspase‐8 to activate the ZBP1‐NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1‐NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase‐6. Additionally, influenza viral proteins, such as M2, NS1, and PB1‐F2, have also been shown to regulate the ZBP1‐NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1‐NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1‐NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases.

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ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis)

Cited by 304 publications

References 98 publications

Toward targeting inflammasomes: insights into their regulation and activation

Toward targeting inflammasomes: insights into their regulation and activation

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

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