NEK7: a potential therapy target for NLRP3-related diseases

Liu, Ganglei; Chen, Xueliang; Wang, Qianqian; Yuan, Long

doi:10.5582/bst.2020.01029

Cited by 40 publications

(30 citation statements)

References 91 publications

(117 reference statements)

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“…Accumulating evidence has revealed large numbers of inhibitors of NLRP3 inflammasome activation through various pharmacological approaches used with NLRP3 inflammasomerelated disease models. 13,241,242 Several extensive reviews summarizing NLRP3 inflammasome activators and inhibitors have suggested that developing new small molecules that directly target NLRP3 seems to be more specific, cost-effective, and safer than an overall cytokine blockade. 241,242 Determination of the complexity of the NLRP3 inflammasome structure and interactions among its components holds promise for the development of new molecules targeting specific components or interactions of the NLRP3 inflammasome complex.…”

Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

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Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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“…Uric acid crystals and soluble UA can activate the immune system and increase the production of the reactive oxygen species (ROS), which can stimulate neutrophil chemotaxis and activate NLR family pyrin domain containing 3 (NLRP3) inflammasomes ( 5 , 6 ). Never in mitosis gene A (NIMA)-related kinase 7 (NEK7) is a protein kinase that acts as a selective upstream regulator of NLRP3 inflammasome activation ( 7 ). Previous studies have revealed that NEK7 can connect the adjacent NLRP3 subunits and mediate NLRP3 inflammasome activation through mitotic interaction ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species induced by uric acid promote NRK‑52E cell apoptosis through the NEK7‑NLRP3 signaling pathway

Wang

et al. 2021

Mol Med Rep

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increasing uric acid (ua) could induce renal tubular epithelial cell (NRK-52E) injury. However, the specific mechanism by which UA induces renal tubular epithelial cell injury remains unknown. It was hypothesized that UA induces renal tubular epithelial cell injury through reactive oxygen species (ROS) and the Never in mitosis gene A (NIMA)-related kinase 7 (NEK7)/NLR family pyrin domain containing 3 (NLRP3) signaling pathway. TUNEL assay and flow cytometry were applied to measure apoptosis, and the results of the present study showed that UA treatment induced apoptosis of NRK-52E cells in a concentration-dependent manner. Western blotting was performed to determine the expression levels of cleaved caspase-3, Bax and Bcl-xl, it was found that levels were significantly increased after UA treatment in NRK-52E cells. ROS and apoptosis were predominantly induced in NRK-52E cells and there was an association between roS and apoptosis. Enhanced expression of NEK7, NLRP3, apoptosis-associated speck-like and caspase-1 were observed in NRK-52E cells treated with ua. The roS inhibitor, n-acetyl-l-cysteine, exerted a protective effect on the UA-induced apoptosis of tubular epithelial cells by reducing excess roS production, which significantly inhibited NEK7 and NLRP3 inflammasome activation. These results indicated that UA activates ROS and induces apoptosis of NRK-52E cells. The mechanism might be related to the regulation of the NEK7/NLRP3 signaling pathway.

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“…Although the mechanisms underlying NLRP inflammasome activation remain largely unclear, several proteins have recently been identified as essential activation regulators. NIMA-related kinase 7 (NEK7), a member of the NEK family, regulates NLRP3 oligomerization and activation downstream of K + efflux [ 32 ]. NEK7 binds to the C-terminal leucine-rich repeats (LRRs) of NLRP3 in a kinase-independent manner, which is likely mediated by mitochondrial ROS [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes

et al. 2021

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The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasome is a key inflammatory signaling pathway activated via a two-step signaling process consisting of priming and activation steps. Several studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH) 2 VD 3 ) inhibits the priming step required for NLRP3 inflammasome activation in immune cells. However, as activating the NLRP1 inflammasome in keratinocytes does not necessarily require a priming step, whether 1,25(OH) 2 VD 3 inhibits NLRP1 activation in unprimed keratinocytes is currently unknown. In this study, we showed that 1,25(OH) 2 VD 3 inhibits nigericin-induced NLRP1 inflammasome activation in unprimed keratinocytes. 1,25(OH) 2 VD 3 suppressed nigericin-induced interleukin-1β (IL-1β) secretion and caspase-1 activation in human primary keratinocytes. In addition, 1,25(OH) 2 VD 3 significantly inhibited the formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomers and specks, but not caspase-1 enzymatic activity, suggesting that 1,25(OH) 2 VD 3 prevents NLRP1-ASC complex assembly in keratinocytes. Vitamin D receptor (VDR)-knockdown abolished the inhibitory effects of 1,25(OH) 2 VD 3 on nigericin-induced ASC oligomerization and IL-1β secretion, suggesting that 1,25(OH) 2 VD 3 suppresses inflammasome activation via VDR signaling. Furthermore, nigericin induced K + efflux and cellular reactive oxygen species (ROS) production, and 1,25(OH) 2 VD 3 pretreatment suppressed nigericin-induced ROS production. 1,25(OH) 2 VD 3 increased the expression of both nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), whereas HO-1 inhibition or NRF2 and HO-1 knockdown abrogated the inhibitory effects of 1,25(OH) 2 VD 3 on IL-1β secretion. Our results indicate that 1,25(OH) 2 VD 3 inhibits nigericin-induced activation step of NLRP1 inflammasome activation in unprimed keratinocytes. Our findings reveal the mechanism underlying the inhibitory effect of 1,25(OH) 2 VD 3 , which involves NRF2-HO-1 pathway activation through the VDR, providing further insight into the potential function of 1,25(OH) 2 VD 3 as a therapeutic agent for inflammasome-related skin diseases.

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NEK7: a potential therapy target for NLRP3-related diseases

Cited by 40 publications

References 91 publications

An update on the regulatory mechanisms of NLRP3 inflammasome activation

An update on the regulatory mechanisms of NLRP3 inflammasome activation

Reactive oxygen species induced by uric acid promote NRK‑52E cell apoptosis through the NEK7‑NLRP3 signaling pathway

1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes

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