scholarly journals A Dual Role for Receptor-interacting Protein Kinase 2 (RIP2) Kinase Activity in Nucleotide-binding Oligomerization Domain 2 (NOD2)-dependent Autophagy

2012 ◽  
Vol 287 (30) ◽  
pp. 25565-25576 ◽  
Author(s):  
Craig R. Homer ◽  
Amrita Kabi ◽  
Noemí Marina-García ◽  
Arun Sreekumar ◽  
Alexey I. Nesvizhskii ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Activity ◽  
Nucleotide Binding ◽  
Dual Role ◽  
Interacting Protein ◽  
Oligomerization Domain

scholarly journals The Wnt–NLK Signaling Pathway Inhibits A-Myb Activity by Inhibiting the Association with Coactivator CBP and Methylating Histone H3

2005 ◽  
Vol 16 (10) ◽  
pp. 4705-4713 ◽  
Author(s):  
Toshihiro Kurahashi ◽  
Teruaki Nomura ◽  
Chie Kanei-Ishii ◽  
Yoichi Shinkai ◽  
Shunsuke Ishii
Keyword(s):  
Protein Kinase ◽  
Gene Family ◽  
Family Member ◽  
Kinase Activity ◽  
Histone H3 ◽  
Promoter Regions ◽  
Interacting Protein ◽  
Myb Gene ◽  
Proliferation And Differentiation ◽  
Negative Form

The c-myb proto-oncogene product (c-Myb) regulates proliferation and differentiation of hematopoietic cells. Recently we have shown that c-Myb is degraded in response to Wnt-1 stimulation via a pathway involving TAK1 (TGF-β-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). NLK and HIPK2 bind directly to c-Myb and phosphorylate c-Myb at multiple sites, inducing its ubiquitination and proteasome-dependent degradation. The mammalian myb gene family contains two members in addition to c-myb, A-myb, and B-myb. Here, we report that the Wnt-NLK pathway also inhibits A-Myb activity, but by a different mechanism. As in the case of c-Myb, both NLK and HIPK2 bound directly to A-Myb and inhibited its activity. NLK phosphorylated A-Myb, but did not induce A-Myb degradation. Overexpression of NLK inhibited the association between A-Myb and the coactivator CBP, thus, blocking A-Myb-induced trans-activation. The kinase activity of NLK is required for the efficient inhibition of the association between A-Myb and CBP, although the kinase-negative form of NLK also partly inhibits the interaction between A-Myb and CBP. Furthermore, NLK induced the methylation of histone H3 at lysine-9 at A-Myb-bound promoter regions. Thus, the Wnt-NLK pathway inhibits the activity of each Myb family member by different mechanisms.

scholarly journals Hydrogen sulfide mitigates myocardial inflammation by inhibiting nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome activation in diabetic rats

2020 ◽  
Vol 245 (3) ◽  
pp. 221-230 ◽  
Author(s):  
Qiang Jia ◽  
Shomaila Mehmood ◽  
Xiaofen Liu ◽  
Shanfeng Ma ◽  
Rui Yang
Keyword(s):  
Hydrogen Sulfide ◽  
Nlrp3 Inflammasome ◽  
Fasting Blood Glucose ◽  
Nucleotide Binding ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Interacting Protein ◽  
Sodium Hydrosulfide ◽  
Thioredoxin Interacting Protein ◽  
Oligomerization Domain

Inflammation plays a crucial part in hyperglycemia-induced myocardial damage. Hydrogen sulfide has been found to possess multiple biological activities in previous studies. This study investigated whether hydrogen sulfide conferred cardiac protection against damage in a diabetic rat model by inhibiting nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome activation. Male animals were assigned to control, streptozotocin, streptozotocin + sodium hydrosulfide, and streptozotocin + DL-propargylglycine groups. Animals in the three streptozotocin groups were administrated 55 mg/kg streptozotocin by intraperitoneal injection. Streptozotocin + sodium hydrosulfide and streptozotocin + propargylglycine groups were treated with sodium hydrosulfide (56 μmol/kg) and propargylglycine (40 mg/kg), respectively, for four weeks. Estimation of fasting blood glucose, heart-weight/body-weight, cardiac function, and histopathological analysis, and measurement of myocardial enzymes were done to evaluate the degree of cardiac injury. In order to investigate the redox changes, the levels of total antioxidant capacity, malondialdehyde and lipid peroxidation, and the activities of superoxide dismutase, catalase, and glutathione peroxidase were assessed; the protein expression levels of Thioredoxin and Thioredoxin-interacting protein were measured in myocardial tissue. In addition, inflammatory reactions were assessed by measuring the concentration levels of interleukin-6, tumor necrosis factor-α, interleukin-1β, and interleukin-18 in serum and the expression levels of NLRP3 inflammasome complex-associated proteins in cardiac tissue. In the heart, hyperglycemia significantly induced cardiac dysfunction and injury, redox perturbation, and aggravation of inflammatory reactions. However, except for fasting blood glucose, treatment with sodium hydrosulfide significantly ameliorated these alterations, whereas treatment with propargylglycine further aggravated these alterations. This study highlights the protective properties of hydrogen sulfide against hyperglycemia-induced cardiac injury, and its possible mechanism was shown to involve negative regulation of Thioredoxin-interacting protein-mediated NLRP3 inflammasome activation. Impact statement Diabetic cardiomyopathy is a serious complication of diabetic patients, accompanied by chronic inflammation. The nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome complex is involved in the progression of the inflammatory response of diabetes, including diabetic cardiomyopathy. Hydrogen sulfide (H2S) is a novel endogenous gas messenger. Several pieces of evidence have exhibited that H2S exerts anti-oxidant and anti-inflammatory activities against hyperglycemia-induced myocardial injury, but the mechanism remains unclear. The current study indicated that H2S protected the myocardium against hyperglycemia-induced injury by preventing Thioredoxin-interacting protein (TXNIP)-mediated NLRP3 inflammasome complex activation. The inhibition of TXNIP-mediated NLRP3 inflammasome complex would be an efficient therapy for H2S treatment in diabetic cardiomyocytes.

scholarly journals CARD6 Is Interferon Inducible but Not Involved in Nucleotide-Binding Oligomerization Domain Protein Signaling Leading to NF-κB Activation

2007 ◽  
Vol 28 (5) ◽  
pp. 1541-1552 ◽  
Author(s):  
Almut Dufner ◽  
Gordon S. Duncan ◽  
Andrew Wakeham ◽  
Alisha R. Elford ◽  
Håkan T. Hall ◽  
...  
Keyword(s):  
Nucleotide Binding ◽  
Adenovirus Type ◽  
Lymphocytic Choriomeningitis ◽  
Immune Defense ◽  
Protein Signaling ◽  
Interacting Protein ◽  
Serovar Typhimurium ◽  
Bacterial Peptidoglycan ◽  
Oligomerization Domain

ABSTRACT We have previously reported the cloning and characterization of CARD6, a caspase recruitment domain (CARD)-containing protein that is structurally related to the interferon (IFN)-inducible GTPases. CARD6 associates with microtubules and with receptor-interacting protein 2 (RIP2). RIP2 mediates NF-κB activation induced by the intracellular nucleotide-binding oligomerization domain (NOD) receptors that sense bacterial peptidoglycan. Here we report that the expression of CARD6 and RIP2 in bone marrow-derived macrophages is rapidly induced by beta IFN and gamma IFN. This IFN-induced upregulation of CARD6 is suppressed by lipopolysaccharide (LPS), in contrast to LPS's enhancement of IFN-induced RIP2 upregulation. We generated CARD6-deficient (CARD6−/−) mice and carried out extensive analyses of signaling pathways mediating innate and adaptive immune responses, including the NOD pathways, but did not detect any abnormalities. Moreover, CARD6−/− mice were just as susceptible as wild-type mice to infection by Salmonella enterica serovar Typhimurium, Listeria monocytogenes, Candida albicans, lymphocytic choriomeningitis virus, or mouse adenovirus type 1. Thus, although structural and in vitro analyses strongly suggest an important role for CARD6 in immune defense, the physiological function of CARD6 remains obscure.

scholarly journals K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yong Tang ◽  
Hailin Tu ◽  
Jie Zhang ◽  
Xueqiang Zhao ◽  
Yini Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Control Cell ◽  
Embryonic Lethality ◽  
Interacting Protein ◽  
Early Embryonic Lethality ◽  
Massive Cell Death ◽  
Massive Cell ◽  
Dependent Signaling Pathway

Abstract Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death through its kinase activity. However, how its kinase activity is regulated remains poorly understood. Here, we generate Ripk1K376R/K376R knock-in mice in which the Lys(K)63-linked ubiquitination of RIPK1 is impaired. The knock-in mice display an early embryonic lethality due to massive cell death that is resulted from reduced TAK1-mediated suppression on RIPK1 kinase activity and forming more TNFR1 complex II in Ripk1K376R/K376R cells in response to TNFα. Although TNFR1 deficiency delays the lethality, concomitant deletion of RIPK3 and Caspase8 fully prevents embryonic lethality of Ripk1K376R/K376R mice. Notably, Ripk1K376R/- mice are viable but develop severe systemic inflammation that is mainly driven by RIPK3-dependent signaling pathway, indicating that K63-linked ubiquitination on Lys376 residue of RIPK1 also contributes to inflammation process. Together, our study reveals the mechanism by which K63-linked ubiquitination on K376 regulates RIPK1 kinase activity to control cell death programs.

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