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.

scholarly journals Discovery of a Family of Mixed Lineage Kinase Domain-like Proteins in Plants and Their Role in Innate Immune Signaling

2020 ◽  
Vol 28 (6) ◽  
pp. 813-824.e6 ◽  
Author(s):  
Lisa K. Mahdi ◽  
Menghang Huang ◽  
Xiaoxiao Zhang ◽  
Ryohei Thomas Nakano ◽  
Leïla Brulé Kopp ◽  
...  
Keyword(s):  
Kinase Domain ◽  
Innate Immune ◽  
Immune Signaling ◽  
Mixed Lineage Kinase ◽  
Innate Immune Signaling

scholarly journals RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling

2021 ◽  
Vol 118 (28) ◽  
pp. e2101189118
Author(s):  
Kaiwen W. Chen ◽  
Benjamin Demarco ◽  
Saray Ramos ◽  
Rosalie Heilig ◽  
Michiel Goris ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Effector Proteins ◽  
Innate Immune ◽  
Target Cells ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Common Strategy

Injection of effector proteins to block host innate immune signaling is a common strategy used by many pathogenic organisms to establish an infection. For example, pathogenic Yersinia species inject the acetyltransferase YopJ into target cells to inhibit NF-κB and MAPK signaling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1–caspase-8 death–inducing platform that confers antibacterial defense. While recent studies revealed that caspase-8 cleaves the pore-forming protein gasdermin D to trigger pyroptosis in macrophages, whether RIPK1 activates additional substrates downstream of caspase-8 to promote host defense is unclear. Here, we report that the related gasdermin family member gasdermin E (GSDME) is activated upon detection of YopJ activity in a RIPK1 kinase–dependent manner. Specifically, GSDME promotes neutrophil pyroptosis and IL-1β release, which is critical for anti-Yersinia defense. During in vivo infection, IL-1β neutralization increases bacterial burden in wild-type but not Gsdme-deficient mice. Thus, our study establishes GSDME as an important mediator that counteracts pathogen blockade of innate immune signaling.

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 Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6

2008 ◽  
Vol 205 (5) ◽  
pp. 1077-1086 ◽  
Author(s):  
Fabiana S. Machado ◽  
Lísia Esper ◽  
Alexandra Dias ◽  
Rajat Madan ◽  
YuanYuan Gu ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Proteasomal Degradation ◽  
Innate Immune ◽  
Cytokine Signaling ◽  
Immune Signaling ◽  
Innate Immune Signaling

Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor–associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.

scholarly journals FIP200 restricts RNA virus infection by facilitating RIG-I activation

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lingyan Wang ◽  
Kun Song ◽  
Wenzhuo Hao ◽  
Yakun Wu ◽  
Girish Patil ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rna Virus ◽  
Innate Immune ◽  
Host Susceptibility ◽  
In Vivo Studies ◽  
Helicase Domain ◽  
Type I ◽  
Immune Signaling ◽  
Innate Immune Signaling

AbstractRetinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression. Currently, the regulatory mechanisms controlling RIG-I activation remain to be fully elucidated. Here we show that the FAK family kinase-interacting protein of 200 kDa (FIP200) facilitates RIG-I activation. FIP200 deficiency impaired RIG-I signaling and increased host susceptibility to RNA virus infection. In vivo studies further demonstrated FIP200 knockout mice were more susceptible to RNA virus infection due to the reduced innate immune response. Mechanistic studies revealed that FIP200 competed with the helicase domain of RIG-I for interaction with the two tandem caspase activation and recruitment domains (2CARD), thereby facilitating the release of 2CARD from the suppression status. Furthermore, FIP200 formed a dimer and facilitated 2CARD oligomerization, thereby promoting RIG-I activation. Taken together, our study defines FIP200 as an innate immune signaling molecule that positively regulates RIG-I activation.

scholarly journals Ethanol Induction of Innate Immune Signals Across BV2 Microglia and SH-SY5Y Neuroblastoma Involves Induction of IL-4 and IL-13

2019 ◽  
Vol 9 (9) ◽  
pp. 228 ◽  
Author(s):  
Colleen J. Lawrimore ◽  
Leon G. Coleman ◽  
Jian Zou ◽  
Fulton T. Crews
Keyword(s):  
Target Genes ◽  
High Mobility ◽  
Ethanol Exposure ◽  
Innate Immune ◽  
Human Neuroblastoma ◽  
Immune Signaling ◽  
Neuronal Signaling ◽  
Innate Immune Signaling ◽  
Bv2 Microglia

Innate immune signaling molecules, such as Toll-like receptors (TLRs), cytokines and transcription factor NFκB, are increased in post-mortem human alcoholic brain and may play roles in alcohol dependence and neurodegeneration. Innate immune signaling involves microglia -neuronal signaling which while poorly understood, may impact learning and memory. To investigate mechanisms of ethanol induction of innate immune signaling within and between brain cells, we studied immortalized BV2 microglia and SH-SY5Y human neuroblastoma to model microglial and neuronal signaling. Cells were treated alone or in co-culture using a Transwell system, which allows transfer of soluble mediators. We determined immune signaling mRNA using real-time polymerase chain reaction. Ethanol induced innate immune genes in both BV2 and SH-SY5Y cultured alone, with co-culture altering gene expression at baseline and following ethanol exposure. Co-culture blunted ethanol-induced high mobility group box protein 1 (HMGB1)-TLR responses, corresponding with reduced ethanol induction of several proinflammatory NFκB target genes. In contrast, co-culture resulted in ethanol upregulation of cytokines IL-4 and IL-13 in BV2 and corresponding receptors, that is, IL-4 and IL-13 receptors, in SH-SY5Y, suggesting induction of a novel signaling pathway. Co-culture reduction in HMGB1-TLR levels occurs in parallel with reduced proinflammatory gene induction and increased IL-4 and IL-13 ligands and receptors. Findings from these immortalized and tumor-derived cell lines could provide insight into microglial-neuronal interactions via release of soluble mediators in vivo.

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