Physiological and Pathological Roles of Mammalian NEK7

Sun, Zhenzhen; Gong, Wenbin; Zhang, Yue

doi:10.3389/fphys.2020.606996

Cited by 19 publications

(21 citation statements)

References 89 publications

(167 reference statements)

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“…Since microtubules (MT) and Microtubules Organizing Center (MTOC) are important in speck formation in monocytes [22][23][24] , we analyzed MT dynamics in neutrophils stained with SiR-tubulin (Video 2 available online, Figure 5F and supplemental Table S2). We observed that ASC speck was assembled in 56% of cells near the MTOC and mostly colocalized with MTs radiating from the MTOC (Video 2 available online, Figure 5F).…”

Section: Inflammasome Activation Occurs Transiently Near the Microtubule Organizing Center Early During Netosis In Lps-stimulated Murine mentioning

confidence: 99%

Inflammasome activation in neutrophils of patients with severe COVID-19

Aymonnier

Fredenburgh

et al. 2022

Blood Advances

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Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-COV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation, (i.e. ASC speck assembly), and timing relative to NETosis in stimulated neutrophils by real time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that approximately 2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was observed in neutrophils with an intact poly-lobulated nucleus, suggesting early formation during neutrophil activation. Additionally, 40% of nuclei were positive for citrullinated histone H3, and there was a significant correlation between speck formation and nuclear histone citrullination. Time-lapse microscopy in LPS-stimulated neutrophils from fluorescent ASC reporter mice showed that ASC speck formed transiently and at the microtubule organizing center, long before NET release. Our study shows that ASC speck is present in neutrophils from COVID-19 patients with respiratory failure and that it forms early in NETosis. Our findings suggest that inhibition of neutrophil inflammasomes may be beneficial in COVID-19.

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Section: Inflammasome Activation Occurs Transiently Near the Microtubule Organizing Center Early During Netosis In Lps-stimulated Murine mentioning

confidence: 99%

Inflammasome activation in neutrophils of patients with severe COVID-19

Aymonnier

Fredenburgh

et al. 2022

Blood Advances

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“…As a consequence, both proteins are quite small. Nek6 is 313 residues, while Nek7, the smallest of the NIMA-related kinases, is 302 amino acids long [ 138 ]. Nek6 is a mostly globular, somewhat elongated protein with a disordered N-terminus, which it uses to interact with its cellular partners [ 139 ].…”

Section: Mammalian Nek6 and Nek7mentioning

confidence: 99%

“…Nek7 is also involved in activation of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome and inflammatory disease [ 138 ]. When Nek7 is phosphorylated at Ser-204 by Polo-like kinase 4 (PLK4), Nek7 exhibits reduced affinity for NLRP3, an innate immune sensor.…”

Section: Mammalian Nek6 and Nek7mentioning

confidence: 99%

In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals

Bachus

Graves

Fulham

et al. 2022

IJMS

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The Never in mitosis gene A (NIMA) family of serine/threonine kinases is a diverse group of protein kinases implicated in a wide variety of cellular processes, including cilia regulation, microtubule dynamics, mitotic processes, cell growth, and DNA damage response. The founding member of this family was initially identified in Aspergillus and was found to play important roles in mitosis and cell division. The yeast family has one member each, Fin1p in fission yeast and Kin3p in budding yeast, also with functions in mitotic processes, but, overall, these are poorly studied kinases. The mammalian family, the main focus of this review, consists of 11 members named Nek1 to Nek11. With the exception of a few members, the functions of the mammalian Neks are poorly understood but appear to be quite diverse. Like the prototypical NIMA, many members appear to play important roles in mitosis and meiosis, but their functions in the cell go well beyond these well-established activities. In this review, we explore the roles of fungal and mammalian NIMA kinases and highlight the most recent findings in the field.

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“…Comprehending and disturbing the NEK7-NLRP3 cooperation could present a unique strategy to target NLRP3 activity. Researchers have come to ground-breaking conclusions on the modulation of gene transcription or protein expression effects of NLRP3 inflammasome signaling cascade operating through NEK7 effects in NLRP3-associated maladies, like tumors, inflammatory diseases, and autoimmune diseases, such as squamous cell carcinoma of head and neck, hepatocellular carcinoma, diabetic retinopathy, systemic lupus erythematosus, gout, atherosclerosis, type 2 diabetes, metabolic syndrome, age-related macular degeneration, Alzheimer’s disease, multiple sclerosis, and inflammatory bowel disease [ 260 , 261 ].…”

Section: Inhibitors Of Nlrp3 Inflammasome-driven In Vivo Disease Modelsmentioning

confidence: 99%

Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models

et al. 2021

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Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Certain members of the NLR family have been documented to lump into multimolecular conglomerates called inflammasomes, which are inherently linked to stimulation of the cysteine protease caspase-1. Following activation, caspase-1 severs the proinflammatory cytokines interleukin (IL)-1β and IL-18 to their biologically active forms, with consequent commencement of caspase-1-associated pyroptosis. This type of cell death by pyroptosis epitomizes a leading pathway of inflammation. Accumulating scientific documentation has recorded overstimulation of NLRP3 (NOD-like receptor protein 3) inflammasome involvement in a wide array of inflammatory conditions. IL-1β is an archetypic inflammatory cytokine implicated in multiple types of inflammatory maladies. Approaches to impede IL-1β’s actions are possible, and their therapeutic effects have been clinically demonstrated; nevertheless, such strategies are associated with certain constraints. For instance, treatments that focus on systemically negating IL-1β (i.e., anakinra, rilonacept, and canakinumab) have been reported to result in an escalated peril of infections. Therefore, given the therapeutic promise of an NLRP3 inhibitor, the concerted escalated venture of the scientific sorority in the advancement of small molecules focusing on direct NLRP3 inflammasome inhibition is quite predictable.

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Physiological and Pathological Roles of Mammalian NEK7

Cited by 19 publications

References 89 publications

Inflammasome activation in neutrophils of patients with severe COVID-19

Inflammasome activation in neutrophils of patients with severe COVID-19

In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals

Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models

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