The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1

Carpentier, Samuel J.; Ni, Minjian; Duggan, Jeffrey M.; James, Richard G.; Cookson, Brad T.; Hamerman, Jessica A.

doi:10.1126/scisignal.aau0615

Cited by 17 publications

(17 citation statements)

References 51 publications

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“…BCAP deficiency results in exaggerated innate immune response, leading to higher CD4 + activation (35) and to more proliferative cells (31). As a macrophage signaling adaptor protein, it can dampen NLRP3 and NLRC4 inflammasome activation through interaction with the caspase-1 inhibitor (36). Altogether, BCAP could play a part in influencing systemic inflammation, which PFAPA syndrome is known for.…”

Section: Discussionmentioning

confidence: 99%

PIK3AP1 and SPON2 Genes Are Differentially Methylated in Patients With Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) Syndrome

et al. 2020

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Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common autoinflammatory disease in children and is often grouped together with hereditary periodic fever syndromes, although its cause and hereditary nature remain unexplained. We investigated whether differential DNA methylation was present in DNA from peripheral blood mononuclear cells (PBMC) in patients with PFAPA vs. healthy controls. A whole-epigenome analysis (MeDIP and MBD) was performed using pooled DNA libraries enriched for methylated genomic regions and identified candidate genes, two of which were further evaluated with methylation-specific restriction enzymes coupled with qPCR (MSRE-qPCR). The analysis showed that the PIK3AP1 and SPON2 gene regions are differentially methylated in patients with PFAPA. MSRE-qPCR proved to be a quick, reliable, and cost-effective method of confirming results from MeDIP and MBD. Our findings indicate that a B-cell adapter protein (PIK3AP1), as the PI3K binding inhibitor of inflammation, and spondin-2 (SPON2), as a pattern recognition molecule and integrin ligand, could play a role in the etiology of PFAPA. Their role and the impact of changed DNA methylation in PFAPA etiology and autoinflammation need further investigation.

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Section: Discussionmentioning

confidence: 99%

PIK3AP1 and SPON2 Genes Are Differentially Methylated in Patients With Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) Syndrome

et al. 2020

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“…It is possible that NAIP1 may be regulated differently to the other NAIPs, which is supported by the observation that NAIP1 required additional priming signals, such as poly(I:C) 31 . Lastly, negative regulators of the NLRC4 inflammasome have also been identified, including the B cell adaptor for phosphoinositide 3‐kinase, 66 heat shock cognate protein 70, 67 the S Typhimurium SopB protein, 68 and the tick protein sialostatin L2 69 …”

Section: Other Regulatory Mechanismsmentioning

confidence: 94%

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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“…In addition to post-translational and posttranscriptional regulation, a number of molecules can directly or indirectly interact with different components of the NLRP3 inflammasome, through which they impede the assembly of NLRP3 with ASC and caspase-1. For example, the B-cell adapter for phosphoinositide 3-kinase (BCAP) interacts with the caspase-1 pseudosubstrate inhibitor Flightless-1, thereby delaying the recruitment and activation of pro-caspase-1 within the "pre-inflammasome" containing only NLRP3 and ASC, and contributing to delayed clearance of pathogens 159 . The Crohn's disease risk factor IRGM, directly interacts with NLRP3 and ASC, blocks their oligomerization and impedes inflammasome assembly, and alternatively mediates selective autophagy of NLRP3 and ASC, thus providing protection in gut inflammatory disorders 160 .…”

Section: Negative Regulation Of Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Inflammasome activation and regulation: toward a better understanding of complex mechanisms

2020

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Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.

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The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1

Cited by 17 publications

References 51 publications

PIK3AP1 and SPON2 Genes Are Differentially Methylated in Patients With Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) Syndrome

PIK3AP1 and SPON2 Genes Are Differentially Methylated in Patients With Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) Syndrome

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

Inflammasome activation and regulation: toward a better understanding of complex mechanisms

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