Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

Kim, Man Lyang; Chae, Jae Jin; Park, Yong Hwan; Nardo, Dominic De; Stirzaker, Roslynn A.; Ko, Hyun-Ja; Tye, Hazel; Cengia, Louise; DiRago, Ladina; Metcalf, Donald; Roberts, Andrew W.; Kastner, Daniel L.; Lew, Andrew M.; Lyras, Dena; Kile, Benjamin T.; Croker, Ben A.; Masters, Seth L.

doi:10.1083/jcb.2095oia104

Cited by 17 publications

(22 citation statements)

References 38 publications

(53 reference statements)

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“…Although actin polymerization drugs and inhibitors of actin targets were unable to block pyrin activation, a recent genetic disease phenotype observed in mice linked to actin dynamics, was shown to be pyrin dependent. Mutations in the mouse Wdr1, which facilitates actin disassembly, have been shown to result in autoinflammation and increased release of IL‐18 in a pyrin‐dependent manner, suggesting that in this context pyrin activation involves actin disassembly . Other recent studies have shown that colchicine blocks both activation of the mouse and human pyrin inflammasome after RhoA inactivation , suggesting microtubule dynamics somehow control pyrin activation.…”

Section: Role Of the Cytoskeleton In Pyrin Inflammasome Activationmentioning

confidence: 99%

Function and mechanism of the pyrin inflammasome

2017

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Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Recent insights have now revealed how pyrin is activated during infection, providing a molecular basis for the understanding of such disease-causing mutations in pyrin. Interestingly, pyrin does not directly recognize molecular patterns (pathogenor host-derived danger molecules), but rather responds to disturbances in cytoplasmic homeostasis caused by the infection. In the case of pyrin, these perturbations, recently defined as 'homeostasis-altering molecular processes' (HAMPs), are processes leading to the inactivation of the RhoA GTPase. This review attempts to combine early observation and findings with the most recent discoveries on how pyrin detects inactivation of RhoA to shed light on the function and mechanism of pyrin activation.Keywords: FMF r Inflammasome r MEFV r Pyrin r Pyroptosis IntroductionThe observation of inherited pathogenic periodic fevers and inflammation prevalent in Mediterranean regions led to first clinical descriptions of a disease now known as familial Mediteranean fever (FMF) [1], one of the most common hereditary autoinflammatory syndromes. Further studies revealed that FMF, was an autosomal recessive disease associated with mutations in the MEFV gene, which encodes a protein named pyrin [2,3]. Pyrin belongs to the group of cytosolic pattern recognition receptors (PRRs) that control innate immune responses upon the detection of pathogen or host derived danger signals, so called pathogen/danger-associated molecular patterns (PAMPs/DAMPs). Upon activation, several of these receptors, including pyrin, assemble multiprotein signaling complexes called inflammasomes, which recruit and activate caspase-1, a proinflammatory protease [4]. Active caspase-1 drives inflammation by promoting the proteolytic maturation and secretion of cytokines Correspondence: Dr. Petr Broz e-mail: petr.broz@unil.ch such as interleukin (IL)-1β and IL-18, and by initiating a necrotic type of cell death known as pyroptosis. Pyroptosis is caused by the Gasdermin-D (GSDMD) protein which, upon cleavage by caspase-1, forms large permeability pores in the cellular plasma membrane [5][6][7][8][9].Recent literature provides new perspectives on the type of ligands that activate pyrin and on its unusual activation mechanism which is distinct from other well-characterized inflammasome forming PRRs. Moreover, new studies also find evidence for a unique participation of the cytoskeleton during pyrin inflammasome activation. This review sets out to integrate previous observations and discoveries on the pyrin inflammasome with most recent findings. Additionally, we attempt to pinpoint shortcomings and potential gaps in the literature which will need to be addressed in the future.Protein ...

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Section: Role Of the Cytoskeleton In Pyrin Inflammasome Activationmentioning

confidence: 99%

Function and mechanism of the pyrin inflammasome

2017

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“…Similarly to the NLRP3 and Nlrp1b inflammasomes, the pyrin inflammasome does not respond to a specific ligand. Instead, it is activated in response to cytoskeleton alterations and to the inactivation of RhoA (Kim et al, ; Xu et al, ).…”

Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Winsor

Krustev

Bruce

et al. 2019

Cellular Microbiology

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Inflammasomes are cytosolic, multimeric protein complexes capable of activating pro‐inflammatory cytokines such as IL‐1β and IL‐18, which play a key role in host defence. Inflammasome components are highly expressed in the intestinal epithelium. In recent years, studies have begun to demonstrate that epithelial‐intrinsic inflammasomes play a critical role in regulating epithelial homeostasis, both by defending the epithelium from pathogenic insult and through the regulation of the mucosal environment. However, the majority of research regarding inflammasome activation has focused on professional immune cells, such as macrophages. Here, we present an overview of the current understanding of inflammasome function in epithelial cells and at mucosal surfaces and, in particular, in the intestine.

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“…The role of the cytoskeleton in the activation of the Pyrin inflammasome has also been observed in a mouse model of systemic autoinflammatory disease. Mice carrying an inactivating mutation in the actin‐depolymerizing cofactor WD repeat‐containing protein 1 develop a systemic autoinflammatory disease that can be delayed by genetic deletion of Pyrin, ASC, caspase‐1, or IL‐18 . This finding suggests that dysregulated actin dynamics may be sensed by the Pyrin inflammasome, which could lead to inflammation and tissue damage.…”

Section: Pyrin Inflammasomementioning

confidence: 99%

Molecular mechanisms of inflammasome signaling

Mathur

Hayward

Man

2017

Journal of Leukocyte Biology

148

123

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The inflammasome is a macromolecular protein complex that mediates proteolytic cleavage of pro-IL-1β and -IL-18 and induces cell death in the form of pyroptosis. Certain nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), or tripartite motif (TRIM) family receptors trigger the assembly of an inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recent studies have revealed a multitude of host components and signals that are essential for controlling canonical and noncanonical inflammasome activation and pyroptosis. These include pore-forming gasdermin proteins, the never in mitosis A-related kinase 7 (NEK7), IFN-inducible proteins (IFIs), reactive oxygen species (ROS), autophagy, potassium efflux, mitochondrial perturbations, and microbial metabolites. Here, we provide a comprehensive overview of the molecular and signaling mechanisms that provide stringent regulation over the activation and effector functions of the inflammasome.

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Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

Cited by 17 publications

References 38 publications

Function and mechanism of the pyrin inflammasome

Function and mechanism of the pyrin inflammasome

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Molecular mechanisms of inflammasome signaling

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