ASC is an adaptor protein which contains two protein-protein interaction domains; N-terminal - pyrin domain (PYC) and C-terminal - caspase recruitment domain (CARD).. ASC plays an important role in inflammation and apoptosis. It is a component of several inflammatory complexes, inflammasomes, which are important for caspase-1 activation, processing and secretion of pro-inflammatory cytokines (IL-1β, IL-18). It promotes pyropoptosis in macrophages and induces caspase-mediated apoptosis (involving caspase-8 and caspase-9).. Additionally, ASC is involved in transcriptional control of cytokine and chemokine expression independent of the inflammasome.. ...
Background: Inflammatory responses play a key role in the pathophysiology of myocardial ischemia-reperfusion (I/R) injury. ASC is an adaptor protein that forms inflammasome whose activation leads to caspase-1-dependent interleukin (IL)-1β generation and subsequent inflammatory responses; however, the role of ASC in myocardial I/R injury remains to be determined.. Methods and Results: ASC deficient (ASC−/−) and wild-type (WT) mice were subjected to 30 min LAD occlusion, followed by reperfusion. ASC−/− mice showed improved LV dysfunction (%FS: 34.0% vs. 25.7% at 14 days p,0.01), reduced infarct area/area at risk (IA/AAR: 18.7% vs. 28.6% at 48 h, p,0.01), and scar formation (scar/LV area: 9.7% vs. 14.6% at 14 days, p,0.01) after myocardial I/R. Immunostaining revealed decreased infiltration of macrophages (Mac3) and neutrophils (Gr-1), but not neovascularization (CD31), in the injured myocardium of the ASC−/− mice. Real-time RT-PCR and ELISA analyses demonstrated that the myocardial ...
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cdna:known chromosome:VEGA66:16:3945610:3976632:-1 gene:OTTMUSG00000042324 gene_biotype:protein_coding transcript_biotype:protein_coding gene_symbol:Nlrc3 description:NLR family, CARD domain containing 3 ...
NALP1兔多克隆抗体(ab36852)可与人样本反应并经WB, IHC, ICC/IF实验严格验证,被4篇文献引用。所有产品均提供质保服务,中国75%以上现货。
ASC2兔多克隆抗体(ab47092)可与小鼠, 大鼠, 人, 沙鼠样本反应并经WB, IP, IHC实验严格验证。所有产品均提供质保服务,中国75%以上现货。
I need some help. I have a ASC case where the MD did a cystourethroscopy w/ bilaterial retrograde ureterograms. He also did Litholapaxy with the extra
Inflammasome activation is associated with numerous diseases. However, in vivo detection of the activated inflammasome complex has been limited by a dearth of tools. We developed transgenic mice that ectopically express the fluorescent adaptor protein, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and characterized the formation of assembled inflammasome complexes ("specks") in primary cells and tissues. In addition to hematopoietic cells, we found that a stromal population in the lung tissues forms specks during the early phase of influenza infection whereas myeloid cells showed speck formation after two days. In a peritonitis and Group B streptococcus infection models, a higher percentage of neutrophils formed specks at early phases of infection, while dendritic cells formed specks at later time points. Furthermore, speck-forming cells underwent pyroptosis, and extensive release of specks to the extracellular milieu in vivo. These data underscore the ...
The hypothesis of this study was that sustained activity of the Nod-like receptor protein (NLRP)-3 inflammasome in wounds of diabetic humans and mice contributes to the persistent inflammatory response and impaired healing characteristic of these wounds. Macrophages (Mp) isolated from wounds on diabetic humans and db/db mice exhibited sustained inflammasome activity associated with low level of expression of endogenous inflammasome inhibitors. Soluble factors in the biochemical milieu of these wounds are sufficient to activate the inflammasome, as wound conditioned medium activates caspase-1 and induces release of IL-1β and IL-18 in cultured Mp via a reactive oxygen species-mediated pathway. Importantly, inhibiting inflammasome activity in wounds of db/db mice using topical application of pharmacological inhibitors improved healing of these wounds, induced a switch from pro-inflammatory to healing-associated Mp phenotypes and increased levels of pro-healing growth factors. Furthermore, data ...
NLRP3 inflammasome assembly. CARD, caspase recruitment domain; LRR, leucine-rich repeat; NACHT/NBD, nucleotide binding domain; PYD, pyrin domain; CAP1, caspase-
PYCARD, often referred to as ASC (Apoptosis-associated speck-like protein containing a CARD), is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome . NMR structure of full-length ASC: PDB ID 2KN6 [1] This gene encodes an adaptor protein that is composed of two protein-protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD). The PYD and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the inflammatory and apoptotic signaling pathways via the activation of caspase. In normal cells, this protein is localized to the cytoplasm; however, in cells undergoing apoptosis, it forms ...
Chronic low-grade inflammation is considered a driver of many age-related disorders, including vascular diseases (inflammaging). Inhibition of autophagic capacity with ageing was postulated to generate a pro-inflammatory condition via activation of inflammasomes, a group of Interleukin-1 activating intracellular multi-protein complexes. We thus investigated gene expression of inflammasome components in PBMC of 77 vascular patients (age 22-82) in association with age. Linear regression of real-time qRT-PCR data revealed a significant positive association of gene expression of each of the inflammasome components with age (Pearson correlation coefficients: AIM2: r = 0.245; P = 0.032; NLRP3: r = 0.367; P = 0.001; ASC (PYCARD): r = 0.252; P = 0.027; CASP1: r = 0.296; P = 0.009; CASP5: r = 0.453; P = 0.00003; IL1B: r = 0.247; P = 0.030). No difference in gene expression of AIM2, NLRP3, ASC CASP1, and CASP5 was detected between PBMC of patients with advanced atherosclerosis and other vascular patients, whereas
To the Editor. We read the article of Osuka et al. (1) entitled "A Protective Role for Inflammasome Activation Following Injury" with great interest. However, we are concerned that the authors have not sufficiently ruled out the possibility that the major effects attributed to inflammasome inhibition were merely due to the solvent used.. The authors describe inflammasome activation in burned mice 1 day after injury as revealed by caspase 1 activation and increased interleukin 1β (IL-1β) production. Interestingly, the data suggest that inhibiting caspase 1 activity-and thereby inhibiting inflammasome activation-with the Ac-YVAD-cmk peptide did not reduce inflammation as expected. On the contrary, it caused a significantly higher mortality and increased expression of the proinflammatory cytokines IL-6 and IL-33 as compared with untreated burned mice. The authors therefore conclude that inflammasome activation might have a protective role following severe injury. Inhibition of (pro)caspase 1 ...
The cytosolic pattern recognition receptor NLRP3 senses host-derived danger signals and certain microbe-derived products in both humans and rodents. NLRP3 activation assembles an inflammasome complex that contains the adapter proteins ASC and caspase-1, whose activation triggers the maturation and release of the proinflammatory cytokines IL-1β and IL-18. S5 phosphorylation of NLRP3 prevents its oligomerization and activation, whereas dephosphorylation of this residue by the phosphatase PP2A allows NLRP3 activation. However, the protein kinase that mediates NLRP3 S5 phosphorylation is unknown. In this study, we show that AKT associates with NLRP3 and phosphorylates it on S5, limiting NLRP3 oligomerization. This phosphorylation event also stabilizes NLRP3 by reducing its ubiquitination on lysine 496, which inhibits its proteasome-mediated degradation by the E3 ligase Trim31. Pharmacologic manipulation of AKT kinase activity reciprocally modulates NLRP3 inflammasome-mediated IL-1β production. ...
Inflammatory responses play a key role in many neural pathologies, with localized signaling from the non-immune cells making critical contributions. The NLRP3 inflammasome is an important component of innate immune signaling and can link neural insult to chronic inflammation. The NLRP3 inflammasome requires two stages to contribute: priming and activation. The priming stage involves upregulation of inflammasome components while the activation stage results in the assembly and activation of the inflammasome complex. The priming step can be rate limiting and can connect insult to chronic inflammation, but our knowledge of the signals that regulate NLRP3 inflammasome priming in sterile inflammation is limited. This study examined the link between mechanical strain and inflammasome priming in neural systems. Transient non-ischemic elevation of intraocular pressure (IOP) increased mRNA for inflammasome components IL-1β, NLRP3, ASC and CASP1 in rat and mouse retinas. The elevation was greater one day after
Chronic inflammation and inflammasome activation play roles in the pathogenesis of type 2 diabetes (2,29,30). NLRP3 is a member of the NLR family, which is responsible for cytosolic inflammasome activation. The NLRP3 inflammasome has been the focus of particular attention with regard to its roles in inflammatory responses, antimicrobial responses, and a variety of human diseases, including hereditary autoinflammatory syndromes, atherosclerosis, and diabetes (7,22,30,31). Recently, obesity-induced danger signals have been reported to activate the NLRP3 inflammasome and induce the production of IL-1β in adipose tissue in type 2 diabetic patients and mice fed a high-fat diet (9). Circulating levels of C-X-C motif chemokine 10 and CCL2, as well as interferon-γ mRNA and protein levels in adipose tissue, were significantly reduced in NLRP3-deficient mice, suggesting that the NLRP3 inflammasome plays a role in the macrophage-T-cell interactions that are associated with sustained levels of chronic ...
The ASC (apoptosis speck-like protein) is a key component of multimeric protein complexes that mediate inflammation and host defence. Comprising a PYD (Pyrin) domain and a CARD (caspase activation and recruitment domain), ASC functions downstream of NLRs (nucleotide-binding domain, leucine-rich repeat-containing receptors) and AIM2 (absent in melanoma 2) through the formation of supramolecular structures termed inflammasomes. However, the mechanism underlying ASC signalling and its dependency on oligomeric arrangements in inflammasome formation remain poorly understood. When expressed in cells, ASC forms discrete foci (called specks) typically with one speck per cell. We employed a BiFC (bimolecular fluorescence complementation) system to investigate and visualize ASC foci formation in living cells. We demonstrated that the CARD of ASC plays a central role in ASC inflammasome assembly, representing the minimal unit capable of forming foci in conjunction with the caspase 1 CARD. Mutational ...
The term pyroptosis (pyro greek for fire or fever) has been originally coined to describe the non‐apoptotic, caspase‐1‐dependent cell death of Salmonella‐infected macrophages that would alarm and recruit neighboring cells to the site of infection (Cookson & Brennan, 2001). Later it became apparent that the activation of caspase‐1 to induce pyroptosis is controlled by a subset of PRRs that can induce inflammasome activation (e.g. NLRP3, AIM2 or NLRC4/NAIP). Upon recognition of their cognate ligands, these sensors seed the prion‐like assembly of the inflammasome adapter ASC into a high molecular weight cytosolic complex to which caspase‐1 becomes recruited and is activated by. Auto‐processed caspase‐1 then matures the cytokines IL‐1β and IL‐18 to render them bioactive and induce pyroptotic cell death. Besides this canonical inflammasome activation leading to caspase‐1 maturation, other pro‐inflammatory caspases, murine caspase‐11 and human caspase‐4 and caspase‐5, ...
The term pyroptosis (pyro greek for fire or fever) has been originally coined to describe the non‐apoptotic, caspase‐1‐dependent cell death of Salmonella‐infected macrophages that would alarm and recruit neighboring cells to the site of infection (Cookson & Brennan, 2001). Later it became apparent that the activation of caspase‐1 to induce pyroptosis is controlled by a subset of PRRs that can induce inflammasome activation (e.g. NLRP3, AIM2 or NLRC4/NAIP). Upon recognition of their cognate ligands, these sensors seed the prion‐like assembly of the inflammasome adapter ASC into a high molecular weight cytosolic complex to which caspase‐1 becomes recruited and is activated by. Auto‐processed caspase‐1 then matures the cytokines IL‐1β and IL‐18 to render them bioactive and induce pyroptotic cell death. Besides this canonical inflammasome activation leading to caspase‐1 maturation, other pro‐inflammatory caspases, murine caspase‐11 and human caspase‐4 and caspase‐5, ...
On September 21, 2017, Posted by Birgit Rogell , In Press Releases, With Kommentare deaktiviert für EMBL: Visualization of inflammasome formation in real life ...
Exaggerated inflammasome activation in venous thrombosis in CD39-deficient mice. Extracellular release of ATP and ADP through cell death, injury, or activation is a potent stress response, altering the local microenvironment to activate paracrine and autocrine signaling pathways (18, 19). Binding of extracellular ATP to the plasma membrane receptor ionophore P2X7 activates a potent stress-response-signaling pathway characterized by potassium efflux, which triggers assembly and activity of the inflammasome, a multiprotein oligomer that activates highly proinflammatory cytokines including IL-1β (20). Gupta et al. recently reported increased NLRP3 inflammasome assembly in patients at high altitude at risk for DVT (21). Canonical inflammasome activation requires a "priming" step marked by NF-κB activation and inflammasome component transcription (20). A second signal initiates NLRP3-mediated assembly and oligomerization of inflammasome component fibers, proteolytic cleavage of pro-caspase-1 to ...
TroLucaM. Lemarchand E, Barrington J, Chenery A, Haley M, Coutts G, Allen JE, et al. Extent of Ischemic Brain Injury After Thrombotic Stroke Is Independent of the NLRP3 (NACHT, LRR and PYD Domains-Containing Protein 3) Inflammasome. Stroke. 2019;50:1232-1239.. Inflammation plays a key role in the fight against infection. However, following ischaemic brain injury, inflammation can play a very different role, exacerbating the severity of damage. Inflammation results in long lasting, ongoing damage from the onset of vessel blockage through to and during reperfusion of the ischaemic brain area. One possible player within the inflammation related post-stroke damage is the NLR family pyrin domain containing 3 (NLRP3) inflammasome. During ischaemic brain injury, NLRP3 senses multiple stroke-induced stimuli leading to the recruitment of the adaptor protein ASC (the apoptosis-associated speck-like pro-caspase-1) resulting in caspase 1 production leading to downstream IL-1β and IL-18 production and ...
There is a clear need for interdisciplinary research and publications that bring together scientists who work on the inflammasome. This protein complex, termed the inflammasome and many of its components are implicated in disease disorders, autoimmune and infectious diseases. The structure, activation and regulation of the inflammasome complex have been and are still studied in increasing number of laboratories around the world. Our goal is to provide an issue summarizing every fascinating aspect of inflammasome activation and modulation of the innate immune response to microbial and to danger signals. This issue will bring the experts in inflammasome research up to speed with the most recent findings. However, several reviews are geared towards introducing the new scientists to the inflammasome complex and to the fundamental and essential information that will help them understand and even pursue their studies in this direction. By looking at the two sides of the coin, notably, some authors focused on
THE Fas/APO-1 receptor is one of the major regulators of apoptosis(1-7). We report here that Fas/APO-1-mediated apoptosis requires the activation of a new class of cysteine proteases, including interleukin-1 beta-converting enzyme (ICE)(8-10) which are homologous to the product of the Caenorhabditis elegans cell-death gene ced-3 (refs 11, 12). Triggering of Fas/APO-1 rapidly stimulated the proteolytic activity of ICE. Overexpression of ICE, achieved by electroporation and microinjection, strongly potentiated Fas/APO-1-mediated cell death. In addition, inhibition of ICE activity by protease inhibitors, as well as by transient expression of the pox virus-derived serpin inhibitor CrmA or an antisense ICE construct, substantially suppressed Fas/APO-1-triggered cell death. We conclude that activation of ICE or an ICE-related protease is a critical event in Fas/APO-1-mediated cell death.. ...
Active Caspase-1, rat recombinant protein , Interleukin-1 beta convertase, Interleukin-1 beta-converting enzyme, IL-1BC, p45. validated in (PBV11136r-25), Abgent
Cellulose nanocrystal cationic derivative induces NLRP3 inflammasome-dependent IL-1β secretion associated with mitochondrial ROS production
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Inflammasomes are large protein complexes formed in response to cellular stresses that are platforms for recruitment and activation of caspase 1
Supplementary Material for: Inhibition of Rac1 Signaling Downregulates Inflammasome Activation and Attenuates Lung Injury in Neonatal Rats Exposed to Hyperoxia
Recent study of the CAPS disease spectrum has led to significant advances in our understanding of the NLRP3 inflammasome and IL-1β-mediated inflammation. While translational studies have resulted in vital therapies for patients with CAPS, many questions about the inflammasome and other caspase-1-dependent pathways remain. Inflammasome-mediated IL-18 has largely been overlooked in the context of human disease. In addition, recent studies have demonstrated caspase-1 and inflammasome functions extending beyond cytokine maturation to cellular death pathways, but whether these processes have any bearing on CAPS remains to be seen. Here, we take advantage of mutant NLRP3 knockin mouse lines to investigate these questions.. Our studies demonstrate that dysregulated IL-18 secretion occurs from both patient and Nlrp3 mutant mouse cells in a manner similar to IL-1β. In vitro, a hallmark of CAPS is lack of reliance on the 2-signal paradigm generally required for secretion of active IL-1β. We used this ...
Sigma-Aldrich offers abstracts and full-text articles by [Ying Yang, Dong-Mei Zhang, Jia-Hui Liu, Lin-Shui Hu, Qiao-Chu Xue, Xiao-Qin Ding, Ling-Dong Kong].
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Formation of the inflammasome results in the activation of multiple pathways responsible for co-ordinating our immune response, yet interestingly, there are multiple forms of inflammasomes made up and triggered by different sets of proteins. This initial step of activation has been covered very well before, here. The activated inflammsome goes on to trigger key downstream members of our innate immune system through the recruitment of an important regulatory protease (it cuts up other proteins) - caspase 1, which converts inactive molecules to active, pro-inflammatory ones, such as interleukin-1 beta and interleukin-18. This inflammatory cascade functions to initiate an effective local and systemic immune response through the control of the innate and adaptive immune system; for example, IL-beta is responsible for fever and the recruitment of immune cells to the site of infection, and IL-18 induces the development of key T cell responses ...
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Protein expression of apoptosis-associated genes by Western blot. K562 cells were treated with different reagents for 24 h. Notes: data were normalized to β-a
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The innate immune system employs a diverse set of genetically encoded sensors to detect evidence of infection or cell damage in the different compartments of the cell. Cytosolic sensors and adaptors in myeloid cells integrate information to initiate a strong inflammatory response through the assembly of macromolecular protein complexes called inflammasomes. Activation of inflammasomes culminates in the activation of caspase-1, which enables the maturation and release of proinflammatory cytokines, such as IL-1β and -18, as well as cell death by pyroptosis (Vanaja et al., 2015).. The sensor involved determines the specificity of the inflammasome and is typically a member of two conserved protein families: NLRs (nucleotide-binding domain [NBD]- and leucine-rich repeat [LRR]-containing proteins), and ALRs (AIM2-like receptors). These sensors recruit caspase recruitment domain (CARD)-containing pro-caspase-1 indirectly via the interposition of CARD-containing ASC or NLRC4. A diverse array of cell ...
TY - JOUR. T1 - The oxindole Syk inhibitor OXSI-2 blocks nigericin-induced inflammasome signaling and pyroptosis independent of potassium efflux. AU - Yaron, Jordan R.. AU - Rao, Mounica Y.. AU - Gangaraju, Sandhya. AU - Zhang, Liqiang. AU - Kong, Xiangxing. AU - Su, Fengyu. AU - Tian, Yanqing. AU - Glenn, Honor L.. AU - Meldrum, Deirdre. PY - 2016/2/11. Y1 - 2016/2/11. N2 - The inflammasome is a caspase-1-activating complex that is implicated in a growing number of acute and chronic pathologies. Interest has increased in identifying small molecular inhibitors of inflammasome signaling because of its role in clinically relevant diseases. It was recently reported that the protein tyrosine kinase, Syk, regulates pathogen-induced inflammasome signaling by phosphorylating a molecular switch on the adapter protein ASC. However, several aspects of the role of Syk in inflammasome signaling and the effects of its inhibition remain unclear. The aim of the present study is to explore in detail the effects ...
TY - JOUR. T1 - The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans. AU - Liu, Ling. AU - Dong, Ying. AU - Ye, Mei. AU - Jin, Shi. AU - Yang, Jianbo. AU - Joosse, Maria E.. AU - Sun, Yu. AU - Zhang, Jennifer. AU - Lazarev, Mark. AU - Brant, Steven R.. AU - Safar, Bashar. AU - Marohn, Michael. AU - Mezey, Esteban. AU - Li, Xuhang. PY - 2017/6/1. Y1 - 2017/6/1. N2 - Background and Aims: NLRP3 inflammasome is known to be involved in inflammatory bowel diseases. However, it is controversial whether it is pathogenic or beneficial. This study evaluated the roles of NLRP3 inflammasome in the pathogenesis of inflammatory bowel disease in IL-10-/- mice and humans.Methods: NLRP3 inflammasome in colonic mucosa, macrophages, and colonic epithelial cells were analysed by western blotting. The NLRP3 inflammasome components were studied by sucrose density gradient fractionation, chemical cross-linking, and co-immunoprecipitation. The role of NLPR3 ...
The NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome is a member of the NLR family of innate immune cell sensors. These are crucial regulators of cytokine secretions, which promote ischemic cell death and insulin resistance. This review summarizes recent progress regarding the NLRP3 inflammasome as a potential treatment for ischemic stroke in patients with diabetes, two complicated diseases that often occur together. Stroke worsens glucose metabolism abnormalities, and the outcomes after stroke are more serious for diabetic patients compared with those without diabetes. Inflammation contributes to organ injury after ischemic stroke and diabetes. Recent research has focused on inhibiting the activation of inflammasomes and thus reducing the maturation of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. Studies suggest that inhibition of NLRP3 prevents or alleviates both ischemic stroke and diabetes. Targeting against the
NALP3 is a component of the innate immune system that functions as a pattern recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs).[15] NALP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NALP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NALP3 inflammasome. NALP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NALP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NALP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β.[15] The NALP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channels located in the cell membrane.[16] It ...
Here, we demonstrate that HOIL-1L is specifically required for NLRP3 inflammasome-dependent IL-1β secretion in BMDMs independently of NF-κB activation. Mechanistically, the assembly of the NLRP3/ASC inflammasome and linear ubiquitination of the novel LUBAC substrate, ASC, both require HOIL-1L expression. The loss of these functions in HOIL-1L−/− mice results in resistance to MDP-induced peritonitis and contributes to survival upon LPS-induced systemic inflammation. This is the first demonstration that linear ubiquitination is required for NLRP3/ASC-dependent inflammasome activation, thus expanding the role of LUBAC as an innate immune regulator. This work is also the first to compare the role of HOIL-1L in MEF and macrophage cells. Our data indicate that HOIL-1L is critical for NF-κB activation in MEF cells, consistent with the literature (Fig. 1; Tokunaga et al., 2009; Gerlach et al., 2011; Ikeda et al., 2011). However, this activity is cell type specific because HOIL-1L is not required ...
The PYHIN family protein AIM2 is the only inflammasome sensor that does not belong to the NLR family, nevertheless some structural features are shared. AIM2 is characterized by the presence of an N‐terminal PYD and a C‐terminal HIN200 DNA‐binding domain. Since AIM2 lacks a CARD, it essentially requires, similar to NLRPs, the bridging protein ASC to recruit caspase‐1. Unlike other members of the PYHIN family, AIM2 is preferentially localized in the cytosol and operates as a direct intracellular sensor for cytosolic DNA (Fernandes‐Alnemri et al, 2009; Hornung et al, 2009). So far, no substantial prerequisites for its ligand DNA have been described (e.g. sequence motifs or nucleotide modifications), beside the DNA needs to be double stranded and of more than 80 bp in length to accomplish sufficient AIM2 inflammasome formation to allow caspase‐1 cleavage (Jin et al, 2012). Since AIM2 does not contain a NACHT domain, which could facilitate its multimerization, it was already initially ...
The NOD-like receptors (NLR) represent a major class of cytosolic pattern recognition receptors (PRR) that, like their cell-surface Toll-Like Receptor counterparts, are a central part of the innate immune response. There are more than 20 NLR family members, which recognize a wide variety of pathogen-associated molecular patterns (PAMPs). The pathogen specificity of many NLRs is not known, however, 3 of the NLRs form inflammasomes, protein complexes that activate immune and inflammatory responses. These complexes often activate pyroptosis, or caspase-1-dependent programmed cell death. Activation of any of 4 PRR family members (AIM2, NLRC4 or IPAF, NLRP1, and NLRP3) initiates the formation of an inflammasome. These protein complexes in turn activate caspase-1, leading to up-regulation of the pro-inflammatory cytokines IL1B and IL18. Other NLRs signal through RIP2, activating NFB signaling and ultimately cytokine release. As the inflammasomes were only recently identified, their mechanisms, as ...
Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that ABRO1, a subunit of the BRISC deubiquitinase complex, is necessary for optimal NLRP3‐ASC complex formation, ASC oligomerization, caspase‐1 activation, and IL‐1β and IL‐18 production upon treatment with NLRP3 ligands after the priming step, indicating that efficient NLRP3 activation requires ABRO1. Moreover, we report that ABRO1 deficiency results in a remarkable attenuation in the syndrome severity of NLRP3‐associated inflammatory diseases, including MSU‐ and Alum‐induced peritonitis and LPS‐induced sepsis in mice. Mechanistic studies reveal that LPS priming induces ABRO1 binding to NLRP3 in an S194 phosphorylation‐dependent manner, subsequently recruiting the BRISC to remove K63‐linked ubiquitin chains of NLRP3 upon stimulation with activators. Furthermore, deficiency of BRCC3, the catalytically active ...