scholarly journals Phosphothreonine Lyase Promotes p65 Degradation in a Mitogen-Activated Protein Kinase/Mitogen- and Stress-Activated Protein Kinase 1-Dependent Manner

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Mingyu Hou ◽  
Wenhui Wang ◽  
Feizi Hu ◽  
Yuanxing Zhang ◽  
Dahai Yang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pathogenic Bacteria ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Content Type ◽  
Catalytic Active Site ◽  
Mitogen Activated Protein

ABSTRACT Bacterial phosphothreonine lyases have been identified to be type III secretion system (T3SS) effectors that irreversibly dephosphorylate host mitogen-activated protein kinase (MAPK) signaling to promote infection. However, the effects of phosphothreonine lyase on nuclear factor κB (NF-κB) signaling remain largely unknown. In this study, we detected significant phosphothreonine lyase-dependent p65 degradation during Edwardsiella piscicida infection in macrophages, and this degradative effect was blocked by the protease inhibitor MG132. Further analysis revealed that phosphothreonine lyase promotes the dephosphorylation and ubiquitination of p65 by inhibiting the phosphorylation of mitogen- and stress-activated protein kinase-1 (MSK1) and by inhibiting the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), p38α, and c-Jun N-terminal kinase (JNK). Moreover, we revealed that the catalytic active site of phosphothreonine lyase plays a critical role in regulating the MAPK-MSK1-p65 signaling axis. Collectively, the mechanism described here expands our understanding of the pathogenic effector in not only regulating MAPK signaling but also regulating p65. These findings uncover a new mechanism by which pathogenic bacteria overcome host innate immunity to promote pathogenesis.

scholarly journals Edwardsiella piscicidaType III Secretion System Effector EseK Inhibits Mitogen-Activated Protein Kinase Phosphorylation and Promotes Bacterial Colonization in Zebrafish Larvae

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Huifang Cao ◽  
Fajun Han ◽  
Jinchao Tan ◽  
Mingyu Hou ◽  
Yuanxing Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Bacterial Colonization ◽  
Mapk Signaling ◽  
Host Cells ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Secretion Systems ◽  
Content Type ◽  
T3ss Effector ◽  
Mitogen Activated Protein

ABSTRACTBacteria utilize type III secretion systems (T3SS) to deliver effectors directly into host cells. Hence, it is very important to identify the functions of bacterial (T3SS) effectors to understand host-pathogen interactions.Edwardsiella piscicidaencodes a functional T3SS effector, EseK, which can be translocated into host cells and affect bacterial loads. Here, it was demonstrated that aneseKmutant (the ΔeseKmutant) significantly increased the phosphorylation levels of p38α, c-Jun NH2-terminal kinases (JNK), and extracellular signal-regulated protein kinases 1/2 (ERK1/2) in HeLa cells. Overexpression of EseK directly inhibited mitogen-activated protein kinase (MAPK) signaling pathways in HEK293T cells. The ΔeseKmutant consistently promoted the phosphorylation of MAPKs in zebrafish larva infection models. Further, it was shown that the ΔeseKmutant increased the expression of tumor necrosis factor alpha (TNF-α) in an MAPK-dependent manner. Importantly, the EseK-mediated inhibition of MAPKsin vivoattenuated bacterial clearance in larvae. Taken together, this work reveals that theE. piscicidaT3SS effector EseK promotes bacterial infection by inhibiting MAPK activation, which provides insights into the molecular pathogenesis ofE. piscicidain fish.

scholarly journals Platyphyllenone Induces Autophagy and Apoptosis by Modulating the AKT and JNK Mitogen-Activated Protein Kinase Pathways in Oral Cancer Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 4211
Author(s):  
Yen-Tze Liu ◽  
Hsin-Yu Ho ◽  
Chia-Chieh Lin ◽  
Yi-Ching Chuang ◽  
Yu-Sheng Lo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Oral Cancer ◽  
Protein Expression ◽  
Caspase 3 ◽  
Therapeutic Option ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Cancer Proliferation ◽  
Mitogen Activated Protein

Platyphyllenone is a type of diarylheptanoid that exhibits anti-inflammatory and chemoprotective effects. However, its effect on oral cancer remains unclear. In this study, we investigated whether platyphyllenone can promote apoptosis and autophagy in SCC-9 and SCC-47 cells. We found that it dose-dependently promoted the cleavage of PARP; caspase-3, -8, and -9 protein expression; and also led to cell cycle arrest at the G2/M phase. Platyphyllenone up-regulated LC3-II and p62 protein expression in both SCC-9 and SCC-47 cell lines, implying that it can induce autophagy. Furthermore, the results demonstrated that platyphyllenone significantly decreased p-AKT and increased p-JNK1/2 mitogen-activated protein kinase (MAPK) signaling pathway in a dose-dependent manner. The specific inhibitors of p-JNK1/2 also reduced platyphyllenone-induced cleavage of PARP, caspase-3, and caspase -8, LC3-II and p62 protein expression. These findings are the first to demonstrate that platyphyllenone can induce both autophagy and apoptosis in oral cancers, and it is expected to provide a therapeutic option as a chemopreventive agent against oral cancer proliferation.

scholarly journals Induction of Interleukin 10 byBorrelia burgdorferiIs Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
Bikash Sahay ◽  
Kathleen Bashant ◽  
Nicole L. J. Nelson ◽  
Rebeca L. Patsey ◽  
Shiva Kumar Gadila ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lyme Borreliosis ◽  
Human Peripheral Blood ◽  
Interleukin 10 ◽  
Mapk Signaling ◽  
Lyme Arthritis ◽  
Mitogen Activated Protein Kinase ◽  
Content Type ◽  
C3h Mice ◽  
Mitogen Activated Protein

ABSTRACTHost genotype influences the severity of murine Lyme borreliosis, caused by the spirochetal bacteriumBorrelia burgdorferi. C57BL/6 (B6) mice develop mild Lyme arthritis, whereas C3H/HeN (C3H) mice develop severe Lyme arthritis. Differential expression of interleukin 10 (IL-10) has long been associated with mouse strain differences in Lyme pathogenesis; however, the underlying mechanism(s) of this genotype-specific IL-10 regulation remained elusive. Herein we reveal a cAMP-mediated mechanism of IL-10 regulation in B6 macrophages that is substantially diminished in C3H macrophages. Under cAMP and CD14-p38 mitogen-activated protein kinase (MAPK) signaling, B6 macrophages stimulated withB. burgdorferiproduce increased amounts of IL-10 and decreased levels of arthritogenic cytokines, including tumor necrosis factor (TNF). cAMP relaxes chromatin, while p38 increases binding of the transcription factors signal transducer and activator of transcription 3 (STAT3) and specific protein 1 (SP1) to the IL-10 promoter, leading to increased IL-10 production in B6 bone marrow-derived monocytes (BMDMs). Conversely, macrophages derived from arthritis-susceptible C3H mice possess significantly less endogenous cAMP, produce less IL-10, and thus are ill equipped to mitigate the damaging consequences ofB. burgdorferi-induced TNF. Intriguingly, an altered balance between anti-inflammatory and proinflammatory cytokines and CD14-dependent regulatory mechanisms also is operative in primary human peripheral blood-derived monocytes, providing potential insight into the clinical spectrum of human Lyme disease. In line with this notion, we have demonstrated that cAMP-enhancing drugs increase IL-10 production in myeloid cells, thus curtailing inflammation associated with murine Lyme borreliosis. Discovery of novel treatments or repurposing of FDA-approved cAMP-modulating medications may be a promising avenue for treatment of patients with adverse clinical outcomes, including certain post-Lyme complications, in whom dysregulated immune responses may play a role.

Role of nuclear factor κB and mitogen-activated protein kinase signaling in exercise-induced antioxidant enzyme adaptation

2007 ◽  
Vol 32 (5) ◽  
pp. 930-935 ◽  
Author(s):  
Li Li Ji ◽  
Maria-Carmen Gomez-Cabrera ◽  
Jose Vina
Keyword(s):  
Protein Kinase ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Nuclear Factor ◽  
Adaptive Responses ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Exercise Induced

Activation of nuclear factor (NF) κB and mitogen-activated protein kinase (MAPK) pathways in skeletal muscle has been shown to enhance the gene expression of several enzymes that play an important role in maintaining oxidant–antioxidant homeostasis, such as mitochondrial superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS). While an acute bout of exercise activates NFκB and MAPK signaling and upregulates MnSOD and iNOS, administration of chemical agents that suppress reactive oxygen species (ROS) production can cause attenuation of exercise-induced MnSOD and iNOS expression. Thus, ROS generation during exercise may have duel effects: the infliction of oxidative stress and damage, and the stimulation of adaptive responses favoring long-term protection. This scenario explains why animals and humans involved in exercise training have demonstrated increased resistance to oxidative damage under a wide range of physiological and pathological stresses.

scholarly journals Involvement of the Mannose Receptor and p38 Mitogen-Activated Protein Kinase Signaling Pathway of the Microdomain of the Integral Membrane Protein after Enteropathogenic Escherichia coli Infection

2012 ◽  
Vol 80 (4) ◽  
pp. 1343-1350 ◽  
Author(s):  
Zhihua Liu ◽  
Yanlei Ma ◽  
Mary Pat Moyer ◽  
Peng Zhang ◽  
Chenzhang Shi ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mannose Receptor ◽  
Integral Membrane Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Content Type ◽  
Mitogen Activated Protein

ABSTRACTThe microdomain of the integral membrane protein (MIMP) has been shown to adhere to mucin and to antagonize the adhesion of enteropathogenicEscherichia coli(EPEC) to epithelial cells; however, the mechanism has not been fully elucidated. In this study, we further identified the receptor of MIMP on NCM460 cells and investigated the mechanism (the p38 mitogen-activated protein kinase [MAPK] pathway) following the interaction of MIMP and its corresponding receptor, mannose receptor. We first identified the target receptor of MIMP on the surfaces of NCM460 cells using immunoprecipitation-mass spectrometry technology. We also verified the mannose receptor and examined the degradation and activation of the p38 MAPK signaling pathway. The results indicated that MIMP adhered to NCM460 cells by binding to the mannose receptor and inhibited the phosphorylation of p38 MAPK stimulated after EPEC infection via inhibition of the Toll-like receptor 5 pathway. These findings indicated that MIMPs relieve the injury of NCM460 cells after enteropathogenicE. coliinfection through the mannose receptor and inhibition of the p38 MAPK signaling pathway, both of which may therefore be potential therapeutic targets for intestinal diseases, such as inflammatory bowel disease.

scholarly journals Targeting the MEF2-Like Transcription Factor Smp1 by the Stress-Activated Hog1 Mitogen-Activated Protein Kinase

2003 ◽  
Vol 23 (1) ◽  
pp. 229-237 ◽  
Author(s):  
Eulàlia de Nadal ◽  
Laura Casadomé ◽  
Francesc Posas
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Osmotic Stress ◽  
Stationary Phase ◽  
Osmotic Shock ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Yeast Cells ◽  
Dependent Manner ◽  
Mitogen Activated Protein

ABSTRACT Exposure of Saccharomyces cerevisiae to increases in extracellular osmolarity activates the stress-activated Hog1 mitogen-activated protein kinase (MAPK), which is essential for cell survival upon osmotic stress. Yeast cells respond to osmotic stress by inducing the expression of a very large number of genes, and the Hog1 MAPK plays a critical role in gene transcription upon stress. To understand how Hog1 controls gene expression, we designed a genetic screen to isolate new transcription factors under the control of the MAPK and identified the MEF2-like transcription factor, Smp1, as a target for Hog1. Overexpression of SMP1 induced Hog1-dependent expression of osmoresponsive genes such as STL1, whereas smp1Δ cells were defective in their expression. Consistently, smp1Δ cells displayed reduced viability upon osmotic shock. In vivo coprecipitation and phosphorylation studies showed that Smp1 and Hog1 interact and that Smp1 is phosphorylated upon osmotic stress in a Hog1-dependent manner. Hog1 phosphorylated Smp1 in vitro at the C-terminal region. Phosphorylation of Smp1 by the MAPK is essential for its function, since a mutant allele unable to be phosphorylated by the MAPK displays impaired stress responses. Thus, our data indicate that Smp1 acts downstream of Hog1, controlling a subset of the responses induced by the MAPK. Moreover, Smp1 concentrates in the nucleus during the stationary phase, and the lack of SMP1 results in cells that lose viability in the stationary phase. Localization of Smp1 depends on HOG1, and consistently, hog1Δ cells also lose viability during this growth phase. These data suggest that Smp1 could be mediating a role for the Hog1 MAPK during the stationary phase.

scholarly journals Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling

2008 ◽  
Vol 205 (6) ◽  
pp. 1491-1503 ◽  
Author(s):  
Wangsen Cao ◽  
Clare Bao ◽  
Elizaveta Padalko ◽  
Charles J. Lowenstein
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase Inhibitors ◽  
Inflammatory Diseases ◽  
Mapk Pathway ◽  
Critical Role ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Mitogen Activated Protein

The mitogen-activated protein kinase (MAPK) pathway plays a critical role in Toll-like receptor (TLR) signaling. MAPK phosphatase-1 (MKP-1) inhibits the MAPK pathway and decreases TLR signaling, but the regulation of MKP-1 is not completely understood. We now show that MKP-1 is acetylated, and that acetylation regulates its ability to interact with its substrates and deactivate inflammatory signaling. We found that LPS activates acetylation of MKP-1. MKP-1 is acetylated by p300 on lysine residue K57 within its substrate-binding domain. Acetylation of MKP-1 enhances its interaction with p38, thereby increasing its phosphatase activity and interrupting MAPK signaling. Inhibition of deacetylases increases MKP-1 acetylation and blocks MAPK signaling in wild-type (WT) cells; however, deacetylase inhibitors have no effect in cells lacking MKP-1. Furthermore, histone deacetylase inhibitors reduce inflammation and mortality in WT mice treated with LPS, but fail to protect MKP-1 knockout mice. Our data suggest that acetylation of MKP-1 inhibits innate immune signaling. This pathway may be an important therapeutic target in the treatment of inflammatory diseases.

scholarly journals Inhibition of Yeast-to-Hypha Transition and Virulence ofCandida albicansby 2-Alkylaminoquinoline Derivatives

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Lili Meng ◽  
He Zhao ◽  
Shuo Zhao ◽  
Xiuyun Sun ◽  
Min Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Infection Model ◽  
Dependent Manner ◽  
Strong Activity ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
Hyphal Formation ◽  
Protein Kinase Signaling ◽  
Leading Compounds

ABSTRACTA rapid increase inCandida albicansinfection and drug resistance has caused an emergent need for new clinical strategies against this fungal pathogen. In this study, we evaluated the inhibitory activity of a series of 2-alkylaminoquinoline derivatives againstC. albicansisolates. A total of 28 compounds were assessed for their efficacy in inhibiting the yeast-to-hypha transition, which is considered one of the key virulence factors inC. albicans. Several compounds showed strong activity to decrease the morphological transition and virulence ofC. albicanscells. The two leading compounds, compound 1 (2-[piperidin-1-yl]quinolone) and compound 12 (6-methyl-2-[piperidin-1-yl]quinoline), remarkably attenuatedC. albicanshyphal formation and cytotoxicity in a dose-dependent manner, but they showed no toxicity to eitherC. albicanscells or human cells. Intriguingly, compound 12 showed an excellent ability to inhibitC. albicansinfection in the mouse oral mucosal infection model. This leading compound also interfered with the expression levels of hypha-specific genes in the cyclic AMP-protein kinase A and mitogen-activated protein kinase signaling pathways. Our findings suggest that 2-alkylaminoquinoline derivatives could potentially be developed as novel therapeutic agents againstC. albicansinfection due to their interference with the yeast-to-hypha transition.

scholarly journals Topical Spilanthol Inhibits MAPK Signaling and Ameliorates Allergic Inflammation in DNCB-Induced Atopic Dermatitis in Mice

2019 ◽  
Vol 20 (10) ◽  
pp. 2490 ◽  
Author(s):  
Wen-Chung Huang ◽  
Chun-Hsun Huang ◽  
Sindy Hu ◽  
Hui-Ling Peng ◽  
Shu-Ju Wu
Keyword(s):  
Atopic Dermatitis ◽  
Mast Cells ◽  
Protein Kinase ◽  
Allergic Inflammation ◽  
Skin Lesions ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Cox 2

Atopic dermatitis (AD) is a recurrent allergic skin disease caused by genetic and environmental factors. Patients with AD may experience immune imbalance, increased levels of mast cells, immunoglobulin (Ig) E and pro-inflammatory factors (Cyclooxygenase, COX-2 and inducible NO synthase, iNOS). While spilanthol (SP) has anti-inflammatory and analgesic activities, its effect on AD remains to be explored. To develop a new means of SP, inflammation-related symptoms of AD were alleviated, and 2,4-dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in BALB/c mice. Histopathological analysis was used to examine mast cells and eosinophils infiltration in AD-like skin lesions. The levels of IgE, IgG1 and IgG2a were measured by enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used for analysis of the mitogen-activated protein kinase (MAPK) pathways and COX-2 and iNOS protein expression. Topical SP treatment reduced serum IgE and IgG2a levels and suppressed COX-2 and iNOS expression via blocked mitogen-activated protein kinase (MAPK) pathways in DNCB-induced AD-like lesions. Histopathological examination revealed that SP reduced epidermal thickness and collagen accumulation and inhibited mast cells and eosinophils infiltration into the AD-like lesions skin. These results indicate that SP may protect against AD skin lesions through inhibited MAPK signaling pathways and may diminish the infiltration of inflammatory cells to block allergic inflammation.

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