MAPK p38 regulates inflammatory gene expression via tristetraprolin: Doing good by stealth

O’Neil, John D.; Ammit, Alaina J.; Clark, Andrew R.

doi:10.1016/j.biocel.2017.11.003

Cited by 45 publications

(44 citation statements)

References 38 publications

(88 reference statements)

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“…Indeed c-di-AMP turned out to be capable of activating the p38 MAPK, which includes the phosphorylation of p38 and induction and phosphorylation of TTP. Overall this activation is similar to that of LPS (41), albeit with at least one significant difference. The phosphorylation of p38 by LPS is transient, peaks at 30 min, and returns to near-background levels after only 1 h (42), whereas the p38 phosphorylation by c-di-AMP is slower and sustained; it starts early after treatment and continues to be strongly phosphorylated even after 4 h. This is in agreement with the effect of c-di-AMP on the expression of ARE-containing nLuc reporter which was more significant at 8 h post-treatment compared to earlier time points.…”

Section: Discussionsupporting

confidence: 67%

Post-Transcriptional Inflammatory Response to Intracellular Bacterial c-di-AMP

et al. 2020

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Cyclic-di-AMP (c-di-AMP) is a bacterial second messenger that is produced by intracellular bacterial pathogens in mammalian host macrophages. Previous reports have shown that c-di-AMP is recognized by intracellular pattern recognition receptors of the innate immune system and stimulate type I interferon response. Here we report that the response to c-di-AMP includes a post-transcriptional component that is involved in the induction of additional inflammatory cytokines including IL-6, CXCL2, CCL3, and CCL4. Their mRNAs contain AU-rich elements (AREs) in their 3 ′ UTR that promote decay and repress translation. We show that c-di-AMP leads to the phosphorylation of p38 MAPK as well as the induction of the ARE-binding protein TTP, both of which are components of a signaling pathway that modulate the expression of ARE-containing mRNAs at the post-transcriptional level. Pharmacological inhibition of p38 reduces the c-di-AMP-dependent release of induced cytokines, while TTP knockdown increases their release and mRNA stability. C-di-AMP can specifically increase the expression of a nano-Luciferase reporter that contains AREs. We propose a non-canonical intracellular mode of activation of the p38 MAPK pathway with the subsequent enhancement in the expression of inflammatory cytokines. C-di-AMP is widely distributed in bacteria, including infectious intracellular pathogens; hence, understanding of its post-transcriptional gene regulatory effect on the host response may provide novel approaches for therapy.

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Section: Discussionsupporting

confidence: 67%

Post-Transcriptional Inflammatory Response to Intracellular Bacterial c-di-AMP

et al. 2020

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“…When ectopic expression of TTP S316A or TTP S316D in TTO KO cells, the decrease at 1 h was not recovered (Fig.5C). We suggest that the dynamic TTP phosphorylation is required for the bi-phasic TNFα expression [50,51], and the lower amount and hypo-phosphorylated TTP at 1 h induction (Fig.4A) exhibits higher mRNA destabilization activity. Like phosphorylation at serines 52 and 178 by p38-MK2 [27], Ser316 phosphorylation of TTP also displayed cytoplasmic localization (Fig.6C).…”

Section: Discussionmentioning

confidence: 88%

The Functional Characterization of Phosphorylation of Tristetraprolin at C-Terminal NOT1-binding Domain

Hsieh

Chen

Chang

et al. 2020

Preprint

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Backgound: Tristetraprolin (TTP) family proteins contain conserved tandem CCCH zinc-finger binding to AU-rich elements and C-terminal NOT1-binding domain. TTP is phosphorylated extensively in cells and its mRNA destabilization activity is regulated by protein phosphorylation. Methods: We generated an antibody against phospho-Serine 316 located at C-terminal NOT1-binding site and examined TTP phosphorylation in LPS-stimulated RAW264.7 cells. Knockout of TTP in RAW264.7 cells using CRISPR/Cas9 gene editing was created to explore TTP functions. Results: We demonstrated that Ser316 was phosphorylated by p90 ribosomal S6 kinase 1 (RSK1) and p38-activated protein kinase (MK2), and dephosphorylated by Protein Phosphatase 2A (PP2A). Phosphorylation-mimic mutant of S316D resulted in dissociation with CCR4-NOT deadenylase complex through weakening interaction with CNOT1. Furthermore, Ser316 and serines 52 and 178 were independently contributed to CCR4-NOT complex recruitment in the immunoprecipitation assay using phosphor-mimic mutants. In RAW264.7 macrophages, TTP was induced and Ser316 was phosphorylated through RSK1 and MK2 by LPS stimulation. Knockout of TTP resulted in TNFα mRNA increased due to mRNA stabilization. Overexpression of non-phosphorylated S316A TTP mutant can restore TTP activity and lead to TNFα mRNA decreased. GST pull-down and RNA pull-down analyses demonstrated that endogenous TTP with Ser316 phosphorylation decreased the interaction with CNOT1. Conclusions: Our results suggest that the TTP-mediated mRNA stability is modulated by Ser316 phosphorylation to regulate the TTP interaction with CCR4-NOT deadenylase complex.

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“…Some studies suggested that the RNA degradation activity of TTP is negatively regulated by p38 MAPK-dependent signaling (Stoecklin et al, 2004;Brook et al, 2006;Hitti et al, 2006). However, the impact of the p38 pathway on TTP expression and function remains controversial (O'Neil et al, 2018). TTP is found at sites of inflammation, and is colocalized with active p38 MAPK (Ross et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

Luo

Song

et al. 2020

Front. Physiol.

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Hypoxic injury is one of the most important factors in progressive kidney disorders. Since we have found that δ-opioid receptor (DOR) is neuroprotective against hypoxic stress through a differential regulation of mitogen-activated protein kinases (MAPKs) and anti-inflammatory cytokines, we asked if DOR that is highly expressed in the kidney can modulate renal MAPKs and anti-inflammatory cytokines under hypoxia. We exposed cultured rat kidney epithelial cells (NRK-52E) to prolonged hypoxia (1% O 2) with applications of specific DOR agonist or/and antagonist to examine if DOR affects hypoxia-induced changes in MAPKs and anti-inflammatory cytokines. The results showed that endogenous DOR expression remained unchanged under hypoxia, while DOR activation with UFP-512 (a specific DOR agonist) reversed the hypoxia-induced up-regulation of ERK1/2 and p38 phosphorylation. DOR inhibition with naltrindole had no appreciable effect on the hypoxia-induced changes in ERK1/2 phosphorylation, but increased p38 phosphorylation. DOR inhibition with naltrindole attenuated the effects of DOR activation on the changes in ERK1/2 and p38 phosphorylation in hypoxia. Moreover, DOR activation/inhibition differentially affected the expression of transcriptional repressor B-cell lymphoma 6 (Bcl-6), anti-inflammatory cytokines tristetraprolin (TTP), and interleukin-10 (IL-10). Taken together, our novel data suggest that DOR activation differentially regulates ERK1/2, p38, Bcl-6, TTP, and IL-10 in the renal cells under hypoxia.

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MAPK p38 regulates inflammatory gene expression via tristetraprolin: Doing good by stealth

Cited by 45 publications

References 38 publications

Post-Transcriptional Inflammatory Response to Intracellular Bacterial c-di-AMP

Post-Transcriptional Inflammatory Response to Intracellular Bacterial c-di-AMP

The Functional Characterization of Phosphorylation of Tristetraprolin at C-Terminal NOT1-binding Domain

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

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