Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense

Zheng, Min; Karki, Rajendra; Vogel, Peter; Kanneganti, Thirumala‐Devi

doi:10.1016/j.cell.2020.03.040

Cited by 345 publications

(356 citation statements)

References 75 publications

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“…[46][47][48][49][50][51][52][53][54] Of note, NLRP3 inflammasome activation by influenza A virus (IAV) infection is regulated by the Z-DNA binding protein 1 (ZBP1)-containing PANoptosome, a recently identified multi-protein complex that senses IAV and controls induction of pyroptosis, apoptosis, and necroptosis in IAV-infected cells. 55 TAK1 inhibition and a host of additional microbial pathogens also induce NLRP3 inflammasome-mediated pyroptosis concomitant with induction of necroptosis and extrinsic apoptosis in the targeted cell population, a process that was recently coined as PANoptosis. [56][57][58][59] Moreover, gain-of-function mutations in NLRP3 cause autosomal dominantly inherited autoinflammatory diseases that are collectively named Cryopyrin-Associated Periodic Syndrome (CAPS), and which comprise-in increasing order of clinical severity-familial F I G U R E 1 Overview of different inflammasome complexes: (From left to right) Engagement of different TLR receptors leads to activation of IKKs, which in turn results in activation of NF-κB signaling.…”

Section: Nlrp3mentioning

confidence: 99%

Therapeutic modulation of inflammasome pathways

Chauhan

Walle

Lamkanfi

2020

Immunological Reviews

158

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Inflammasomes are macromolecular complexes formed in response to pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs) that drive maturation of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, and cleave gasdermin D (GSDMD) for induction of pyroptosis. Inflammasomes are highly important in protecting the host from various microbial pathogens and sterile insults. Inflammasome pathways are strictly regulated at both transcriptional and post‐translational checkpoints. When these checkpoints are not properly imposed, undue inflammasome activation may promote inflammatory, metabolic and oncogenic processes that give rise to autoinflammatory, autoimmune, metabolic and malignant diseases. In addition to clinically approved IL‐1‐targeted biologics, upstream targeting of inflammasome pathways recently gained interest as a novel pharmacological strategy for selectively modulating inflammasome activation in pathological conditions.

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Section: Nlrp3mentioning

confidence: 99%

Therapeutic modulation of inflammasome pathways

Chauhan

Walle

Lamkanfi

2020

Immunological Reviews

158

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“…We very recently discovered that the host factor caspase-6, the physiological role of which has been enigmatic for decades, acts as a ZBP1-NLRP3 inflammasome regulator (Figure 3). 54 We found that loss of caspase-6 in BMDMs leads to reduced ZBP1-NLRP3 inflammasome activation following IAV infection. 54 The reduced ZBP1-NLRP3 inflammasome assembly is not due to defective priming, since the activation of both NF-κB and pERK is not dampened.…”

Section: Irf1 Expression During Iav Infection Is Largely Dependent Onmentioning

confidence: 73%

“…54 We found that loss of caspase-6 in BMDMs leads to reduced ZBP1-NLRP3 inflammasome activation following IAV infection. 54 The reduced ZBP1-NLRP3 inflammasome assembly is not due to defective priming, since the activation of both NF-κB and pERK is not dampened. 54 Additionally, the induction of ZBP1 expression in Casp6 -/cells is normal following IAV infection.…”

Section: Irf1 Expression During Iav Infection Is Largely Dependent Onmentioning

confidence: 73%

“…48,49 Subsequent studies in our laboratory showed redundant roles for caspase-8 and caspase-1/NLRP3, suggesting intersecting functions for pyroptotic, apoptotic, and necroptotic molecules. 32,50,51 Our more recent studies have demonstrated the roles of ZBP1, 28 TAK1, 52,53 and caspase-6 54 in the process of PANoptosis activation, further solidifying the basis of the concept.…”

Section: Panoptosismentioning

confidence: 74%

“…Most recently, we found that this concept can be applied to various pathogens including IAV, vesicular stomatitis virus (VSV), Listeria monocytogenes, and Salmonella enterica serovar Typhimurium, and we characterized a single cell death complex, the PANoptosome, that initiates this process. 47,55 While our initial work found that NLRP3 is a key molecule in this complex, 53,54 our discovery of PANoptosis in the context of pathogens that are recognized by other inflammasome sensors suggests that these molecules may also play a role in PANoptosome formation. 47,55 PANoptosis is also observed during development.…”

Section: Panoptosismentioning

confidence: 96%

See 2 more Smart Citations

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

Zheng

Kanneganti

2020

Immunological Reviews

Self Cite

298

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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AKT controls NLRP3 inflammasome activation by inducing DDX3X phosphorylation

Guo

Chen

et al. 2021

FEBS Letters

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The NLRP3 inflammasome, a critical component of the innate immune system, induces caspase‐1 activation and interleukin‐1β maturation and drives cell fate toward pyroptosis. However, the mechanism of NLRP3 inflammasome activation still remains elusive. Here we provide evidence that AKT regulates NLRP3 inflammasome activation. Upon NLRP3 activation, AKT activity is inhibited by second stimulus‐induced reactive oxygen species. In contrast, AKT activation leads to NLRP3 inhibition and improved mitochondrial fitness. Mechanistically, AKT induces the phosphorylation of the DDX3X (DEAD‐box helicase 3, X‐linked), a recently identified NLRP3 inflammasome component, and impairs the interaction between DDX3X and NLRP3. Furthermore, an AKT agonist reduces NLRP3‐dependent inflammation in two in vivo models of LPS‐induced sepsis and Alum‐induced peritonitis. Altogether, our study highlights an important role of AKT in controlling NLRP3 inflammasome activation.

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Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense

Cited by 345 publications

References 75 publications

Therapeutic modulation of inflammasome pathways

Therapeutic modulation of inflammasome pathways

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

AKT controls NLRP3 inflammasome activation by inducing DDX3X phosphorylation

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