A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation

Chear, Chai Teng; Nallusamy, Revathy; Canna, Scott; Chan, Kwai Cheng; Baharin, Mohd Farid; Hishamshah, Munirah; Ghani, Hamidah; Ripen, Adiratna Mat; Mohamad, Saharuddin Bin

doi:10.1016/j.clim.2019.108328

Cited by 27 publications

(31 citation statements)

References 17 publications

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“…This mutant LRRs likely have enhanced interaction with the LRRs of an adjacent NLRC4, promoting NLRC4 oligomerization and increased inflammasome activation. Research into the NLRC4‐MAS phenotype has further identified another disease‐causing alteration, p.Gln657Leu, in the LRRs 113 . How this mutation affects the activation mechanism of the NLRC4 inflammasome is currently unknown; however, the patient displayed elevated IL‐18 levels in line with other patients carrying an NLRC4 mutation 113 .…”

Section: Nlrc4 In Autoinflammatory Diseasesmentioning

confidence: 92%

“…Disruption in NLRC4 interface interactions has also been reported within the LRRs leading to MAS‐like autoinflammation 112,113 . For example, the mutation, p.Trp655Cys, induced a loss of NLRC4 autoinhibition 112 .…”

Section: Nlrc4 In Autoinflammatory Diseasesmentioning

confidence: 96%

“…Research into the NLRC4‐MAS phenotype has further identified another disease‐causing alteration, p.Gln657Leu, in the LRRs 113 . How this mutation affects the activation mechanism of the NLRC4 inflammasome is currently unknown; however, the patient displayed elevated IL‐18 levels in line with other patients carrying an NLRC4 mutation 113 . These findings demonstrate that mutations occurring in different regions of NLRC4 can manifest in similar autoinflammatory characteristics (such as in MAS), likely via distinct mechanisms.…”

Section: Nlrc4 In Autoinflammatory Diseasesmentioning

confidence: 99%

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Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Kay

Wang

Kirkby

et al. 2020

Immunological Reviews

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Cytosolic innate immune sensing is a cornerstone of innate immunity in mammalian cells and provides a surveillance system for invading pathogens and endogenous danger signals. The NAIP‐NLRC4 inflammasome responds to cytosolic flagellin, and the inner rod and needle proteins of the type 3 secretion system of bacteria. This complex induces caspase‐1‐dependent proteolytic cleavage of the proinflammatory cytokines IL‐1β and IL‐18, and the pore‐forming protein gasdermin D, leading to inflammation and pyroptosis, respectively. Localized responses triggered by the NAIP‐NLRC4 inflammasome are largely protective against bacterial pathogens, owing to several mechanisms, including the release of inflammatory mediators, liberation of concealed intracellular pathogens for killing by other immune mechanisms, activation of apoptotic caspases, caspase‐7, and caspase‐8, and expulsion of an entire infected cell from the mammalian host. In contrast, aberrant activation of the NAIP‐NLRC4 inflammasome caused by de novo gain‐of‐function mutations in the gene encoding NLRC4 can lead to macrophage activation syndrome, neonatal enterocolitis, fetal thrombotic vasculopathy, familial cold autoinflammatory syndrome, and even death. Some of these clinical manifestations could be treated by therapeutics targeting inflammasome‐associated cytokines. In addition, the NAIP‐NLRC4 inflammasome has been implicated in the pathogenesis of colorectal cancer, melanoma, glioma, and breast cancer. However, no consensus has been reached on its function in the development of any cancer types. In this review, we highlight the latest advances in the activation mechanisms and structural assembly of the NAIP‐NLRC4 inflammasome, and the functions of this inflammasome in different cell types. We also describe progress toward understanding the role of the NAIP‐NLRC4 inflammasome in infectious diseases, autoinflammatory diseases, and cancer.

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Section: Nlrc4 In Autoinflammatory Diseasesmentioning

confidence: 92%

Section: Nlrc4 In Autoinflammatory Diseasesmentioning

confidence: 96%

Section: Nlrc4 In Autoinflammatory Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Kay

Wang

Kirkby

et al. 2020

Immunological Reviews

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“…AIFEC flares have been described to resemble the macrophage activation syndrome (MAS), as evidenced by a prominent IL‐1β signature, myeloid cell activation, cytotoxic T‐cell dysfunction and IFN gamma (IFNγ)‐related hemophagocytosis 203 . Distinctly, IL‐18 serum levels—that drive IFNγ production—and the IL‐18/CXCL9 ratio are highly elevated in AIFEC patients, even compared to NOMID patients, which is reminiscent of adult‐onset stills disease‐related MAS or X‐linked inhibitor of apoptosis deficiency (XIAP) 201,203,204 . Since then, additional patients have been reported with either AD germline or somatic mutations in NLRC4 , with phenotypes similar to NOMID and FCAS syndromes 203‐205 .…”

Section: Primary Immunodeficiencies Caused By Immunological Gain‐of‐fmentioning

confidence: 99%

“…Distinctly, IL‐18 serum levels—that drive IFNγ production—and the IL‐18/CXCL9 ratio are highly elevated in AIFEC patients, even compared to NOMID patients, which is reminiscent of adult‐onset stills disease‐related MAS or X‐linked inhibitor of apoptosis deficiency (XIAP) 201,203,204 . Since then, additional patients have been reported with either AD germline or somatic mutations in NLRC4 , with phenotypes similar to NOMID and FCAS syndromes 203‐205 . In patients with NLRC4 mutations, anakinra was shown to be effective in treating NOMID‐like symptoms, but to a lesser extent in AIFEC flares 203 .…”

Section: Primary Immunodeficiencies Caused By Immunological Gain‐of‐fmentioning

confidence: 99%

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

Made

Hoischen

Netea

et al. 2020

Immunological Reviews

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In the last decade, the paradigm of primary immunodeficiencies (PIDs) as rare recessive familial diseases that lead to broad, severe, and early‐onset immunological defects has shifted toward collectively more common, but sporadic autosomal dominantly inherited isolated defects in the immune response. Patients with PIDs constitute a formidable area of research to study the genetics and the molecular mechanisms of complex immunological pathways. A significant subset of PIDs affect the innate immune response, which is a crucial initial host defense mechanism equipped with pattern‐recognition receptors. These receptors recognize pathogen‐ and damage‐associated molecular patterns in both the extracellular and intracellular space. In this review, we will focus on primary immunodeficiencies caused by genetic defects in cytosolic pattern‐recognition receptor pathways. We discuss these PIDs organized according to their mutational mechanisms and consequences for the innate host response. The advanced understanding of these pathways obtained by the study of PIDs creates the opportunity for the development of new host‐directed treatment strategies.

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Autoinflammatory Contributors to Cytokine Storm

Canna

2024

Advances in Experimental Medicine and Biology

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A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation

Cited by 27 publications

References 17 publications

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

Autoinflammatory Contributors to Cytokine Storm

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