scholarly journals The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis

2019 ◽  
Vol 295 (11) ◽  
pp. 3394-3400 ◽  
Author(s):  
Tejasvi K. Dasari ◽  
Rechel Geiger ◽  
Rajendra Karki ◽  
Balaji Banoth ◽  
Bhesh Raj Sharma ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Recurrent Multifocal Osteomyelitis ◽  
Mouse Strains ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Nonreceptor Tyrosine Kinase ◽  
Downstream Signaling ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Signaling Components

Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2cmo mice, which carry a missense mutation in the proline–serine–threonine phosphatase–interacting protein 2 (Pstpip2) gene. As cmo disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating cmo. However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in Pstpip2cmo mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain–containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in Pstpip2cmo mice, whereas genetic deletion of Syk completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1β signaling in Pstpip2cmo mice, thereby inducing cmo. These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.

scholarly journals NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

2016 ◽  
Vol 113 (16) ◽  
pp. 4452-4457 ◽  
Author(s):  
Prajwal Gurung ◽  
Amanda Burton ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Bone Disease ◽  
Nlrp3 Inflammasome ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Disease Induction ◽  
Multifocal Osteomyelitis ◽  
Chronic Multifocal Osteomyelitis ◽  
Redundant Role

Missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene results in the development of spontaneous chronic bone disease characterized by bone deformity and inflammation that is reminiscent of patients with chronic multifocal osteomyelitis (cmo). Interestingly, this disease is specifically mediated by IL-1β but not IL-1α. The precise molecular pathways that promote pathogenic IL-1β production inPstpip2cmomice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease inPstpip2cmomice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 inPstpip2cmomice provides similar protection as observed in caspase-1 and caspase-8–deficientPstpip2cmomice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease inPstpip2cmomice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseasedPtpn6spinneutrophils. Data from our chimera studies demonstrated that IL-1β produced by hematopoietic cells is sensed by the radioresistant compartment to promote bone disease. Furthermore, our results showed that the IL-1β signaling is unidirectional and feedback signaling of IL-1β onto the hematopoietic compartment is not important for disease induction. In conclusion, our studies have uncovered the combined actions of the NLRP3 inflammasome and caspase 8 leading to IL-1β maturation and the directionality of IL-1β in driving disease inPstpip2cmomice.

Interaction with Sug1 enables Ipaf ubiquitination leading to caspase 8 activation and cell death

2010 ◽  
Vol 427 (1) ◽  
pp. 91-104 ◽  
Author(s):  
Yatender Kumar ◽  
Vegesna Radha ◽  
Ghanshyam Swarup
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Intramolecular Interaction ◽  
Dominant Negative ◽  
26S Proteasome ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Caspase 1 ◽  
Lung Carcinoma Cells ◽  
Lrr Domain

Activation of initiator caspases is dependent on interacting proteins, and Ipaf [ICE (interleukin-1β-converting enzyme)-protease activating factor] {NLRC4 [NLR (Nod-like receptor) family CARD (caspase activation and recruitment domain)-containing 4]} an inflammasome component, is involved in caspase 1 activation and apoptosis. Investigating the mechanisms of Ipaf activation, we found that the C-terminal LRR (leucine-rich repeat) domain of Ipaf, through intramolecular interaction, negatively regulates its apoptosis-inducing function. In A549 lung carcinoma cells, expression of Ac-Ipaf (LRR-domain-deleted Ipaf) induced cell death that was dependent on caspase 8, but not on caspase 1. A yeast two-hybrid screen using Ac-Ipaf as bait identified human Sug1 (suppressor of gal 1), a component of the 26S proteasome, as an interacting protein. In mammalian cells Sug1 interacts and co-localizes with Ipaf. Sug1 binds to amino acids 91–253 of Ipaf, which is also the region that the LRR domain binds to. It potentiates cell death induced by Ipaf and Ac-Ipaf, and co-expression of Sug1 and Ipaf induces caspase-8-dependent cell death. Cellular complexes formed by Ipaf and Sug1 contain caspase 8. Expression of Ac-Ipaf or co-expression of Sug1 with Ipaf results in the formation of cytoplasmic aggregates and caspase 8 activation. Sug1 co-expression enabled modification of Ipaf by ubiquitination. Tagging ubiquitin molecules to Ipaf led to aggregate formation, enhanced caspase 8 interaction and activation, resulting in induction of cell death. Using RNAi (RNA interference) and dominant-negative approaches, we have shown that cell death induced by Ac-Ipaf expression or by treatment with TNF-α (tumour necrosis factor α) or doxorubicin is dependent on Sug1. Our results suggest a role for ubiquitination of Ipaf that is enabled by its interaction with Sug1, leading to caspase 8 activation and cell death.

Macrophage-Stimulating Protein Stimulates Erythropoietin Receptor Phosphorylation To Promote Enhanced Erk1/2 and Akt Activation in a Gab2-Dependent Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1151-1151
Author(s):  
Manprit Chohan ◽  
Adrienne Halupa ◽  
Dwayne L. Barber
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Kinase Activity ◽  
Adaptor Protein ◽  
Erythropoietin Receptor ◽  
Mouse Strains ◽  
Envelope Gene ◽  
Friend Virus ◽  
Macrophage Stimulating Protein ◽  
Downstream Signaling

Abstract Friend-virus mediated erythroleukemia is a well-established model of murine oncogenesis. Several host factors have been shown to be necessary for Friend-mediated infection including a productive interaction between the Erythropoietin Receptor (EPO-R) and the 55 kDa glycoprotein product of the retroviral envelope gene (gp55). The Fv2 locus has been mapped and shown to be a truncated form of the STK tyrosine kinase (Sf-STK). Sf-STK expression and kinase activity is required for Friend virus infection of sensitive mouse strains. While the EPO-R and Sf-STK are required for Friend disease progression, it is unknown whether Sf-STK modulates EPO-R mediated signaling. EPO-R co-immunoprecipitated Sf-STK and STK specifically in COS-7 and Ba/F3 cells expressing both receptors. While the association between EPO-R and STK was shown to be constitutive, intriguingly, we discovered that co-stimulation with the STK ligand, Macrophage-Stimulating Protein (MSP) and EPO resulted in enhanced tyrosine phosphorylation of the EPO-R, compared to stimulation with EPO alone. Interestingly, STK kinase activity was required for EPO-dependent STK tyrosine phosphorylation, but was not required for MSP dependent EPO-R phosphorylation. Analysis of downstream signaling revealed STK and EPO-R co-operated in ligand induced dose-dependent phosphorylation of Erk1/2 and Akt. Interestingly, MSP and EPO also co-operated to stimulate tyrosine phosphorylation of the adaptor protein Gab2, leading to the recruitment of Shp2 and the p85 subunit of Phosphatidylinositol 3 kinase. These data suggest that Gab2 can couple to enhanced phosphorylation of Erk1/2 and Akt. However, no synergy was observed in MSP co-stimulation of JAK2, STAT1, STAT5, Jnk or p38 phosphorylation, demonstrating that STK activates specific EPO-dependent signaling pathways. EPO-dependent regulation of Socs family members was examined in Ba/F3-EPO-R cell lines expressing various STK constructs. The presence of STK induced Cis and Socs3, but not Socs1, transcript levels by 2.0-fold upon EPO stimulation. STK multi-functional docking sites (Y1330/Y1337) were required to observe optimal induction of Socs3. In contrast, Cis induction required STK tyrosine kinase activity. Our data demonstrate that EPO-R and STK interact at a biochemical level leading to augmentation of downstream signaling. These data suggest that Sf-STK contributes to Friend disease through delivery of mitogenic and/or survival signals to target erythroblast progenitor cells.

scholarly journals STS Protects Diabetic Glomerular Vascular Endothelial Barrier by Ameliorating EPC Dysfunction: Targeting RAGE-TXNIP-NLRP3 Inflammasome Pathway

2021 ◽  
Author(s):  
Yan-Yan Heng ◽  
Xiao-Yan Zhang ◽  
Fei-Fei Wang ◽  
Peng-Fei Zhang ◽  
wei wei
Keyword(s):  
Dna Damage ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Vascular Endothelial ◽  
Urine Protein ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation

Abstract Background: Glomerular endothelial cell (GEC) injury is one of the crucial causes of diabetic kidney disease (DKD). Endothelial progenitor cell (EPC) is the essential mechanism of vascular endothelial repair, which damages by diabetic pathology. Sodium Tanshinone Sulfonate ⅡA (STS) is known to protect endothelium, but the mechanism and the role in DKD need to be studied. Methods: EPC was treated with high glucose (HG), and thioredoxin interacting protein (TXNIP), NLR family pyrin domain containing 3 (NLRP3) inflammasome, DNA damage, proliferation, differentiation and senescence were detected; STS and EPC were intravenous injected into diabetic nude mice, the urine protein quantitation and urine protein/creatinine were detected; the Dil-labeled EPC was traced and the expression of TXNIP, caspase-1 (p20), p21, Ki67, CD31 were detected by fluorescence co-location in glomerulus.Results: We found that STS inhibited HG-induced TXNIP expression and NLRP3 inflammasome activation, catalase (CAT) inactivation, DNA damage, senescence； STS restored EPC proliferation and differentiation functions; advanced glycation end products (AGEs) produced in HG treated EPC supernatant, the receptor of AGE (RAGE) blocking inhibited TXNIP expression and NLRP3 inflammasome activation, which mimicked by STS. STS protected EPC functions in diabetic glomerular and enhanced EPC renal function amelioration. Conclusions: We concluded that STS watched CAT activity to prevent HG-induced EPC DNA damage, proliferation, differentiation dysfunction, accelerated senescence by inhibiting the RAGE-TXNIP-NLRP3 inflammasome-caspase-1 pathway.

scholarly journals Functional Mechanisms and Roles of Adaptor Proteins in Abl-Regulated Cytoskeletal Actin Dynamics

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Mizuho Sato ◽  
Masahiro Maruoka ◽  
Tatsuo Takeya
Keyword(s):  
Tyrosine Kinase ◽  
Intracellular Localization ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Actin Dynamics ◽  
Nonreceptor Tyrosine Kinase ◽  
Functional Roles ◽  
Downstream Signaling ◽  
Rich Domain ◽  
Functional Mechanisms

Abl is a nonreceptor tyrosine kinase and plays an essential role in the modeling and remodeling of F-actin by transducing extracellular signals. Abl and its paralog, Arg, are unique among the tyrosine kinase family in that they contain an unusual extended C-terminal half consisting of multiple functional domains. This structural characteristic may underlie the role of Abl as a mediator of upstream signals to downstream signaling machineries involved in actin dynamics. Indeed, a group of SH3-containing accessory proteins, or adaptor proteins, have been identified that bind to a proline-rich domain of the C-terminal portion of Abl and modulate its kinase activity, substrate recognition, and intracellular localization. Moreover, the existence of signaling cascade and biological outcomes unique to each adaptor protein has been demonstrated. In this paper, we summarize functional roles and mechanisms of adaptor proteins in Abl-regulated actin dynamics, mainly focusing on a family of adaptor proteins, Abi. The mechanism of Abl's activation and downstream signaling mediated by Abi is described in comparison with those by another adaptor protein, Crk.

Effect of luteolin on the gene level expression of apoptosis-associated speck-like protein containing a caspase recruitment domain of NLRP3 inflammasome and NF-κB in rats subjected to experimental pancreatitis – influence of HSP70

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sadanandan Rajapriya ◽  
Arumugam Geetha
Keyword(s):  
Body Weight ◽  
Nlrp3 Inflammasome ◽  
Rank Correlation ◽  
Experimental Period ◽  
Serum Levels ◽  
Normal Diet ◽  
Experimental Pancreatitis ◽  
Caspase 1 ◽  
Spearman’S Rank Correlation ◽  
Pyrin Domain

Abstract Objectives Nod-like receptor pyrin domain containing 3 (NLRP3) is one of the well characterized inflammasome that controls the maturation of pro-inflammatory cytokines and thereby the inflammation in pancreas which could be a promising target for anti-inflammatory drugs. The present study is aimed to explore whether luteolin can target the NLRP3 inflammasome and modulate its activity through the signaling protein, HSP70 in the ethanol-cerulein model of experimental pancreatitis. Methods Male albino Wistar rats were divided into four groups. Groups 1 and 2 rats received normal diet. Groups 3 and 4 rats received isocalorically adjusted diet containing ethanol for 5 weeks and cerulein (20 μg/kg body weight i.p., thrice weekly for the last 3 weeks of the experimental period). Additionally, group 2 and 4 rats received 2 mg/kg body weight of luteolin orally from third week. Results Luteolin co-administration decreased the serum levels of HSP70, oxidative stress markers, myeloperoxidase, GSH/GSSG and GST with concomitant downregulation in the mRNA expression of HSP70, caspase-1, ASC-NLRP3 and NF-κB. Spearman’s rank correlation test showed that serum HSP70 has positive correlation with the expression of ASC-NLRP3, caspase-1, NF-κB and 4-hydroxynonenal and negative correlation with GSH:GSSG ratio. Conclusions The modulating effect of luteolin on the expression of HSP70, NF-κB and thereby on ASC-NLRP3 complex may be claimed for its pancreato-protective activity.

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