Thymic stromal lymphopoietin induction by polyinosinic:polycytidylic acid in human keratinocytes is preferentially mediated through protein kinase R and retinoid-inducible gene I and not Toll-like receptor 3

2009 ◽  
Vol 124 (4) ◽  
pp. 862-864 ◽  
Author(s):  
Bettina Seidl ◽  
Behnam Kalali ◽  
Markus Gerhard ◽  
Johannes Ring ◽  
Markus Ollert ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Human Keratinocytes ◽  
Thymic Stromal Lymphopoietin ◽  
Toll Like Receptor ◽  
Protein Kinase R ◽  
Polyinosinic:Polycytidylic Acid ◽  
Inducible Gene

Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli

Glia ◽  
2006 ◽  
Vol 55 (3) ◽  
pp. 239-252 ◽  
Author(s):  
Pamela A. Carpentier ◽  
Bryan R. Williams ◽  
Stephen D. Miller
Keyword(s):  
Protein Kinase ◽  
Toll Like Receptor ◽  
Protein Kinase R

scholarly journals Cytosolic Sensors for Pathogenic Viral and Bacterial Nucleic Acids in Fish

2020 ◽  
Vol 21 (19) ◽  
pp. 7289
Author(s):  
Miriam Mojzesz ◽  
Krzysztof Rakus ◽  
Magdalena Chadzinska ◽  
Kentaro Nakagami ◽  
Gouranga Biswas ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nucleic Acids ◽  
Current Knowledge ◽  
Innate Immune ◽  
Rna Helicases ◽  
Protein Kinase R ◽  
Evolutionarily Conserved ◽  
Different Types ◽  
Molecular Patterns ◽  
Inducible Gene

Recognition of the non-self signature of invading pathogens is a crucial step for the initiation of the innate immune mechanisms of the host. The host response to viral and bacterial infection involves sets of pattern recognition receptors (PRRs), which bind evolutionarily conserved pathogen structures, known as pathogen-associated molecular patterns (PAMPs). Recent advances in the identification of different types of PRRs in teleost fish revealed a number of cytosolic sensors for recognition of viral and bacterial nucleic acids. These are DExD/H-box RNA helicases including a group of well-characterized retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and non-RLR DExD/H-box RNA helicases (e.g., DDX1, DDX3, DHX9, DDX21, DHX36 and DDX41) both involved in recognition of viral RNAs. Another group of PRRs includes cytosolic DNA sensors (CDSs), such as cGAS and LSm14A involved in recognition of viral and intracellular bacterial dsDNAs. Moreover, dsRNA-sensing protein kinase R (PKR), which has a role in antiviral immune responses in higher vertebrates, has been identified in fish. Additionally, fish possess a novel PKR-like protein kinase containing Z-DNA binding domain, known as PKZ. Here, we review the current knowledge concerning cytosolic sensors for recognition of viral and bacterial nucleic acids in teleosts.

scholarly journals Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5

2011 ◽  
Vol 155 (1) ◽  
pp. 31-37 ◽  
Author(s):  
Tuan Anh Le ◽  
Toshiro Takai ◽  
Anh Tuan Vu ◽  
Hirokazu Kinoshita ◽  
Xue Chen ◽  
...  
Keyword(s):  
Human Keratinocytes ◽  
Thymic Stromal Lymphopoietin ◽  
Toll Like Receptor ◽  
Toll Like Receptor 5

scholarly journals Viral Suppression of RIPK1-Mediated Signaling

mBio ◽  
2021 ◽  
Author(s):  
Darshika J. Udawatte ◽  
Alan L. Rothman
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Protein Kinase ◽  
Tumor Necrosis ◽  
Viral Suppression ◽  
Tumor Necrosis Factor Receptor ◽  
Toll Like Receptor ◽  
Upstream Regulator ◽  
Necrosis Factor ◽  
Inducible Gene

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has emerged as a key upstream regulator of cell death and inflammation. RIPK1-mediated signaling governs the outcome of signaling pathways initiated by tumor necrosis factor receptor 1 (TNFR1), Toll-like receptor 3 (TLR3), TLR4, retinoic acid-inducible gene 1 (RIG-I)/melanoma differentiation-associated protein 5 (MDA-5), and Z-binding protein 1 (ZBP1) by signaling for NF-κB activation, mitogen-associated protein kinase (MAPK) and IRF3/7 phosphorylation, and cell death via apoptosis and necroptosis.

scholarly journals Mitochondrial dsRNAs activate PKR and TLR3 to promote chondrocyte degeneration in osteoarthritis

2020 ◽  
Author(s):  
Sujin Kim ◽  
Keonyong Lee ◽  
Yong Seok Choi ◽  
Jayoung Ku ◽  
Yun Jong Lee ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein Kinase ◽  
Inflammatory Cytokines ◽  
Degenerative Diseases ◽  
Toll Like Receptor ◽  
Protein Kinase R ◽  
Molecular Identity ◽  
Synovial Fluids ◽  
Elevated Expression

ABSTRACTProtein kinase R (PKR) is an immune response protein that becomes activated by long double-stranded RNAs (dsRNAs). Several studies reported the misactivation of PKR in patients of degenerative diseases including primary osteoarthritis (OA). However, the molecular identity of PKR-activating dsRNAs remains unknown. Here, we investigate the role of mitochondrial dsRNAs (mt-dsRNAs) in the development of OA. We find that in response to OA-mimicking stressors, cytosolic efflux of mt-dsRNAs is increased, leading to PKR activation and subsequent induction of inflammatory cytokines and apoptosis. Moreover, mt-dsRNAs are exported to the extracellular space where they activate toll-like receptor 3. Elevated expression of mt-dsRNAs in the synovial fluids of OA patients further supports our data. Lastly, we show that autophagy protects chondrocytes from mitochondrial dysfunction partly by removing cytosolic mt-dsRNAs. Together, these findings establish the PKR-mt-dsRNA as a critical regulatory axis in OA development and suggest mt-dsRNAs as a potential target in fighting OA.

scholarly journals A Toll-Like Receptor-Responsive Kinase, Protein Kinase R, Is Inactivated in Endotoxin Tolerance through Differential K63/K48 Ubiquitination

mBio ◽  
2010 ◽  
Vol 1 (5) ◽  
Author(s):  
Darren J. Perkins ◽  
Nilofer Qureshi ◽  
Stefanie N. Vogel
Keyword(s):  
Protein Kinase ◽  
Systemic Infection ◽  
Endotoxin Tolerance ◽  
Toll Like Receptor ◽  
Protein Kinase R ◽  
Tlr Signaling ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Kinetics Of

ABSTRACTOverwhelming inflammation triggered by systemic infection in bacterial sepsis contributes to the pathology of this condition. Toll-like receptors (TLRs) are important in early septic inflammation. As a safeguard, the innate immune system has evolved to counter excessive inflammation through the induction of “tolerance.” In endotoxin tolerance, TLR signaling is inhibited and/or attenuated by multiple mechanisms that mitigate the ability of lipopolysaccharide (LPS) to activate critical kinases through TLR4. Here, we describe a novel mechanism. Protein kinase R (PKR), a kinase normally activated by a subset of TLRs, is rendered unresponsive to LPS in endotoxin-tolerized cells. In its naive state, PKR is subject to K63-linked ubiquitination (Ub), followed by K48-linked Ub, in response to LPS. In tolerance, the kinetics of this differential Ub is altered, resulting in a predominance of K48-linked chains, concomitant with a loss of PKR activation. These findings provide a novel mechanism by which a TLR-responsive kinase may be rendered inactive in tolerance.IMPORTANCE“Endotoxin tolerance” is a period of transient unresponsiveness to the lipopolysaccharide (LPS) outer membrane component of Gram-negative bacteria that is induced by prior exposure to LPS through Toll-like receptor 4 (TLR4). The loss of LPS-inducible cytokine production by macrophages from patients who have experienced Gram-negative sepsis is well documented, and the increased susceptibility of such patients to reinfection has been attributed to the development of endotoxin tolerance. Multiple mechanisms have been proffered to account for this attenuated response. Using the LPS-responsive kinase protein kinase R (PKR), we have identified differential K48 versus K63 ubiquitination as an additional molecular mechanism by which signal-transducing elements may be inactivated in a state of endotoxin tolerance. This work is highly significant because it links recent discoveries concerning the important role of ubiquitination of signaling molecules in regulating TLR signaling with the loss of LPS responsiveness in tolerance.

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