MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism

Li, Xuan; Thome, Sarah; Ma, Xiaodan; Amrute-Nayak, Mamta; Finigan, Alison; Kitt, Lauren; Masters, Leanne; James, John R.; Shi, Yuguang; Meng, Guoyu; Mallat, Ziad

doi:10.1038/ncomms15986

Cited by 110 publications

(137 citation statements)

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“…Microtubule integrity and microtubule‐dependent transport have been shown to be critical for inflammasome activation (Misawa et al , ; Li et al , ). Specifically, inflammasome inducers stimulate α‐tubulin acetylation which mediates microtubule‐dependent transport and NLRP3 inflammasome activation (Misawa et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…A hallmark of inflammasome activation is the formation of one large speck structure in a perinuclear area per cell (Li et al , ; Chen & Chen, ). Little is known about what this cellular structure is and why solely one speck is formed per cell.…”

Section: Introductionmentioning

confidence: 99%

“…A recent study demonstrates that in response to activating stimuli NLRP3 is transported through microtubules to the microtubule‐organizing center (MTOC), namely the centrosome in mammalian cells, for the assembly and activation of inflammasome, enabling the formation of a single inflammasome speck within the cell (Li et al , ). Importantly, the assembly of NLRP3 inflammasome in the centrosome is critical for its optimal activation since improper positioning of NLRP3 due to inhibition of the MARK4, a driver of NLRP3 transporting along microtubules, attenuates inflammasome activation (Li et al , ). These findings link centrosome to inflammasome activation and raise a possibility that inflammasome activity is subject to regulation by the centrosome or centrosome‐localized proteins.…”

Section: Introductionmentioning

confidence: 99%

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PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

Yang

Zhang

et al. 2019

The EMBO Journal

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The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase-1 and drive the maturation of proinflammatory cytokines IL-1b and IL-18. NLRP3 inflammasome activity must be tightly controlled, as its overactivation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo-like kinase 4 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA-mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3-associated inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

Yang

Zhang

et al. 2019

The EMBO Journal

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“…The involvement of the cytoskeleton in activation of inflammasomes has also been reported, since microtubule de‐stabilizing drugs such as nocodazole and colchicine reduce NLRP3 dependent IL‐1β release . A possible mechanism could be that these drugs block the positioning of the NLRP3 inflammasome, which has been proposed to be dependent on the microtubule network .…”

Section: Role Of the Cytoskeleton In Pyrin Inflammasome Activationmentioning

confidence: 95%

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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“…Mitochondrial DNA and ROS are released from damaged mitochondria after exposure to microbial infection, particulate matters, and ATP, which in turn induce the activation of the NLRP3‐inflammasome. ER‐mitochondria contact is induced by mitochondrial damage and mediated by dynein‐dependent microtubule‐dependent spatial arrangement of the ER and mitochondria . NLRP3 localizes mainly in the ER, whereas ASC localizes in the mitochondria, cytosol, and nucleus .…”

Section: Inflammasomes and Autophagymentioning

confidence: 99%

Autophagy limits activation of the inflammasomes

Takahama

Akira

Saitoh

2017

Immunological Reviews

131

106

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Inflammasomes are multiprotein complexes that control the maturation and production of interleukin-1 family members and play crucial roles in host defense against pathogens. However, dysregulated activation of inflammasomes is associated with intense inflammation, leading to the development of inflammatory diseases. Therefore, inflammasomes must be activated at a proper strength to protect against infection and avoid tissue damage. Recent studies have highlighted the cross-talk between inflammasome activation and autophagy, the cellular machinery associated with the degradation of intracellular components and maintenance of cellular homeostasis. Notably, deficiencies in autophagy-related proteins induce the aberrant activation of inflammasomes, causing severe tissue damage. In contrast, autophagy inducers ameliorate symptoms of inflammasome-related diseases. In this review, we discuss recent advances in the involvement of autophagy in regulating inflammasomes activation and in the development of inflammatory diseases.

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MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism

Cited by 110 publications

References 50 publications

PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

Function and mechanism of the pyrin inflammasome

Autophagy limits activation of the inflammasomes

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