HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation

Magupalli, Venkat Giri; Negro, Roberto; Tian, Yuzi; Hauenstein, Arthur V.; Caprio, Giuseppe Di; Skillern, Wesley; Deng, Qiufang; Orning, Pontus; Alam, Hasan B.; Maliga, Zoltan; Sharif, Humayun; Hu, Jun; Evavold, Charles L.; Kagan, Jonathan C.; Schmidt, Florian I.; Fitzgerald, Katherine A.; Kirchhausen, Tomas; Li, Yongqing; Wu, Hao

doi:10.1126/science.aas8995

Cited by 232 publications

(230 citation statements)

References 68 publications

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“…Thereby, this phosphorylation modification of NEK7 suppressed its binding with NLRP3 and inhibited NLRP3 inflammasome activation (Yang et al, 2019). In addition, HDAC6-mediated MTOC localization of NLRP3 may ensure the engagement of centrosomal kinase NEK7 (Magupalli et al, 2020). These studies suggest the important role of NEK7 in NLRP3 inflammasome activation.…”

Section: Nek7 In the Regulation Of Nlrp3 Inflammasome Activationmentioning

confidence: 83%

Physiological and Pathological Roles of Mammalian NEK7

2020

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NEK7 is the smallest NIMA-related kinase (NEK) in mammals. The pathological and physiological roles of NEK7 have been widely reported in many studies. To date, the major function of NEK7 has been well documented in mitosis and NLRP3 inflammasome activation, but the detailed mechanisms of its regulation remain unclear. This review summarizes current advances in NEK7 research involving mitotic regulation, NLRP3 inflammasome activation, related diseases and potential inhibitors, which may provide new insights into the understanding and therapy of the diseases associated with NEK7, as well as the subsequent studies in the future.

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Section: Nek7 In the Regulation Of Nlrp3 Inflammasome Activationmentioning

confidence: 83%

Physiological and Pathological Roles of Mammalian NEK7

2020

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“…The different mechanisms involved in the activation of the NLRP3 inflammasome is a topic of active investigation and thus, in addition to the mechanisms described above, alternative molecular mechanisms have also been unveiled recently. Because of space concerns, we only reviewed here the more established mechanisms, but we refer the reader to [ 99 , 100 , 101 ] for a more detailed description of these novel mechanisms.…”

Section: Inflammasomes and Pyroptotic Cell Deathmentioning

confidence: 99%

Emerging Role of the Inflammasome and Pyroptosis in Hypertension

Miguel

Pelegrı́n

Baroja‐Mazo

et al. 2021

IJMS

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Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.

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“…Inflammasomes consist of a sensor protein, such as NLRP3, which recognizes the insults and activates effector proteins: Caspase-1. The active Caspase-1 cleaves the inflammatory pro-IL-1β and pro-IL-18 to generate their mature forms, as well as gasdermin D, whose N-terminus domains auto-assemble into pores on the plasma membrane for the release of bioactive cytokines, thus inducing an inflammatory form of cell death known as pyroptosis ( Shi et al, 2015 ; Magupalli et al, 2020 ). Two temporally distinct events are required for the full activation of NLRP3-mediated inflammasome.…”

Section: Role Of Ths On Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome

Luca

Davis

Lin

et al. 2021

Front. Cell Dev. Biol.

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The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic–pituitary–thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus.

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HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation

Cited by 232 publications

References 68 publications

Physiological and Pathological Roles of Mammalian NEK7

Physiological and Pathological Roles of Mammalian NEK7

Emerging Role of the Inflammasome and Pyroptosis in Hypertension

Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome

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