scholarly journals IκB Kinase β Phosphorylates the K63 Deubiquitinase A20 To Cause Feedback Inhibition of the NF-κB Pathway

2007 ◽  
Vol 27 (21) ◽  
pp. 7451-7461 ◽  
Author(s):  
Jessica E. Hutti ◽  
Benjamin E. Turk ◽  
John M. Asara ◽  
Averil Ma ◽  
Lewis C. Cantley ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Feedback Inhibition ◽  
Innate Immune ◽  
Negative Regulator ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Iκb Kinase ◽  
Phosphorylation Event

ABSTRACT Misregulation of NF-κB signaling leads to infectious, inflammatory, or autoimmune disorders. IκB kinase β (IKKβ) is an essential activator of NF-κB and is known to phosphorylate the NF-κB inhibitor, IκBα, allowing it to undergo ubiquitin-mediated proteasomal degradation. However, beyond IκBα, few additional IKKβ substrates have been identified. Here we utilize a peptide library and bioinformatic approach to predict likely substrates of IKKβ. This approach predicted Ser381 of the K63 deubiquitinase A20 as a likely site of IKKβ phosphorylation. While A20 is a known negative regulator of innate immune signaling pathways, the mechanisms regulating the activity of A20 are poorly understood. We show that IKKβ phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-κB signaling pathway. Phosphorylation of A20 by IKKβ thus represents part of a novel feedback loop that regulates the duration of NF-κB signaling following activation of innate immune signaling pathways.

scholarly journals Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways

2017 ◽  
Vol 8 (10) ◽  
pp. e3078-e3078 ◽  
Author(s):  
Puja Kumari ◽  
Irene Saha ◽  
Athira Narayanan ◽  
Sathish Narayanan ◽  
Akinori Takaoka ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Essential Role ◽  
Innate Immune ◽  
Immune Signaling ◽  
Innate Immune Signaling

scholarly journals How to rewire the host cell: A home improvement guide for intracellular bacteria

2017 ◽  
Vol 216 (12) ◽  
pp. 3931-3948 ◽  
Author(s):  
Elias Cornejo ◽  
Philipp Schlaermann ◽  
Shaeri Mukherjee
Keyword(s):  
Host Cell ◽  
Signaling Pathways ◽  
Membrane Trafficking ◽  
Defense Mechanisms ◽  
Bacterial Pathogens ◽  
Innate Immune ◽  
Intracellular Bacteria ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
The Unfolded Protein Response

Intracellular bacterial pathogens have developed versatile strategies to generate niches inside the eukaryotic cells that allow them to survive and proliferate. Making a home inside the host offers many advantages; however, intracellular bacteria must also overcome many challenges, such as disarming innate immune signaling and accessing host nutrient supplies. Gaining entry into the cell and avoiding degradation is only the beginning of a successful intracellular lifestyle. To establish these replicative niches, intracellular pathogens secrete various virulence proteins, called effectors, to manipulate host cell signaling pathways and subvert host defense mechanisms. Many effectors mimic host enzymes, whereas others perform entirely novel enzymatic functions. A large volume of work has been done to understand how intracellular bacteria manipulate membrane trafficking pathways. In this review, we focus on how intracellular bacterial pathogens target innate immune signaling, the unfolded protein response, autophagy, and cellular metabolism and exploit these pathways to their advantage. We also discuss how bacterial pathogens can alter host gene expression by directly modifying histones or hijacking the ubiquitination machinery to take control of several host signaling pathways.

scholarly journals Post-translational Control of Innate Immune Signaling Pathways by Herpesviruses

2019 ◽  
Vol 10 ◽  
Author(s):  
Jessica Carriere ◽  
Youliang Rao ◽  
Qizhi Liu ◽  
Xiaoxi Lin ◽  
Jun Zhao ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Translational Control ◽  
Innate Immune ◽  
Immune Signaling ◽  
Innate Immune Signaling

scholarly journals Gp130-Dependent Release of Acute Phase Proteins Is Linked to the Activation of Innate Immune Signaling Pathways

PLoS ONE ◽  
2011 ◽  
Vol 6 (5) ◽  
pp. e19427 ◽  
Author(s):  
Maren Luchtefeld ◽  
Christoph Preuss ◽  
Frank Rühle ◽  
Eskindir P. Bogalle ◽  
Anika Sietmann ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Innate Immune ◽  
Immune Signaling ◽  
Innate Immune Signaling

scholarly journals A role for thioredoxin-interacting protein (Txnip) in cellular creatine homeostasis

2013 ◽  
Vol 305 (2) ◽  
pp. E263-E270 ◽  
Author(s):  
Sevasti Zervou ◽  
Tanmoy Ray ◽  
Natasha Sahgal ◽  
Liam Sebag-Montefiore ◽  
Rebecca Cross ◽  
...  
Keyword(s):  
Feedback Inhibition ◽  
Global Gene Expression ◽  
Negative Regulator ◽  
Specific Response ◽  
Mrna Levels ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Creatine Uptake

Creatine is important for energy metabolism, yet excitable cells such as cardiomyocytes do not synthesize creatine and rely on uptake via a specific membrane creatine transporter (CrT; SLC6A8). This process is tightly controlled with downregulation of CrT upon continued exposure to high creatine via mechanisms that are poorly understood. Our aim was to identify candidate endogenous CrT inhibitors. In 3T3 cells overexpressing the CrT, creatine uptake plateaued at 3 h in response to 5 mM creatine but peaked 33% higher ( P < 0.01) in the presence of cycloheximide, suggesting CrT regulation depends on new protein synthesis. Global gene expression analysis identified thioredoxin-interacting protein (Txnip) as the only significantly upregulated gene (by 46%) under these conditions ( P = 0.036), subsequently verified independently at mRNA and protein levels. There was no change in Txnip expression with exposure to 5 mM taurine, confirming a specific response to creatine rather than osmotic stress. Small-interfering RNA against Txnip prevented Txnip upregulation in response to high creatine, maintained normal levels of creatine uptake, and prevented downregulation of CrT mRNA. These findings were relevant to the in vivo heart since creatine-deficient mice showed 39.71% lower levels of Txnip mRNA, whereas mice overexpressing the CrT had 57.6% higher Txnip mRNA levels and 28.7% higher protein expression compared with wild types (mean myocardial creatine concentration 124 and 74 nmol/mg protein, respectively). In conclusion, we have identified Txnip as a novel negative regulator of creatine levels in vitro and in vivo, responsible for mediating substrate feedback inhibition and a potential target for modulating creatine homeostasis.

scholarly journals RIP3 Associates with RIP1, TRIF, MAVS, and Also IRF3/7 in Host Innate Immune Signaling in Large Yellow Croaker Larimichthys crocea

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1199
Author(s):  
Pengfei Zou ◽  
Kaiqing Li ◽  
Ying Li ◽  
Yingjia Shen ◽  
Ziping Zhang ◽  
...  
Keyword(s):  
Mrna Level ◽  
Kinase Domain ◽  
Innate Immune ◽  
Poly I:C ◽  
Large Yellow Croaker ◽  
Larimichthys Crocea ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Pseudomonas Plecoglossicida

Receptor-interacting protein 3 (RIP3) has been demonstrated to be a key regulator not only in cell death pathways including apoptosis and necroptosis but also in inflammation and host immune responses. In this study, a RIP3 ortholog named Lc-RIP3 is identified in large yellow croaker (Larimichthys crocea). The open reading frame (ORF) of Lc-RIP3 is 1524 bp long and encodes a protein of 507 amino acids (aa). The deduced Lc-RIP3 protein has an N-terminal kinase domain and a C-terminal RHIM domain, and the genome organization of Lc-RIP3 is conserved in teleosts with 12 exons and 11 introns but is different from that in mammals, which comprises 10 exons and 9 introns. Confocal microscopy revealed that Lc-RIP3 is a cytosolic protein. The expression analysis at the mRNA level indicated that Lc-RIP3 is ubiquitously distributed in various tissues/organs, and could be up-regulated under poly I:C, LPS, PGN, and Pseudomonas plecoglossicida stimulation in vivo. Notably, Lc-RIP3 could induce NF-κB but not IRF3 activation. In addition, Lc-RIP3 co-expression with Lc-TRIF, Lc-MAVS, or Lc-IRF3 significantly abolishes the activation of NF-κB but enhances the induction of IRF3 activity. Moreover, NF-κB activity could be up-regulated when Lc-RIP3 is co-expressed with Lc-RIP1 or Lc-IRF7. These results collectively indicate that Lc-RIP3 acts as an important regulator in host innate immune signaling in teleosts.

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