The Mnks Are Novel Components in the Control of TNFα Biosynthesis and Phosphorylate and Regulate hnRNP A1

Buxadé, María; Parra, Josep Lluis; Rousseau, Stéphane; Shpiro, Natalia; Marquez, Rodolfo; Morrice, Nick; Bain, Jenny; Espel, Enric; Proud, Christopher G.

doi:10.1016/j.immuni.2005.06.009

Cited by 188 publications

(236 citation statements)

References 39 publications

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“…Our results indicate an important role for the Mnk kinases in the generation of the biological effects of IFNs, but the downstream mechanisms remain to be elucidated. The initiation factor eIF4E is an obvious candidate for future studies but other Mnk substrates such as Sprouty 2 [99], hnRNPA1 [34] and PSF [36] may also be important for IFN- responses. Notably, eIF4E has been shown to play an important role in mediating mRNA nuclear export [100], independently of its role in translation, and future studies should address a potential involvement of eIF4E in the nuclear export of ISGs.…”

Section: Rantesmentioning

confidence: 99%

“…Work by Buxade et al (2005) showed that TNFα production in activated T-cells is partially inhibited by inhibition of either p38 or Erk MAPK, while concurrent inhibition of p38 and Erk completely abolished TNFα production [34]. Pharmacological inhibition of Mnk or Mnk1 knockdown demonstrated similar effects, suggesting an important role for Mnk kinases in TNFα production [34].…”

Section: Introductionmentioning

confidence: 99%

“…Pharmacological inhibition of Mnk or Mnk1 knockdown demonstrated similar effects, suggesting an important role for Mnk kinases in TNFα production [34]. Interestingly, this study demonstrated that although the Mnk inhibitor completely abolished the phosphorylation of eIF4E and suppressed TNFα production by 70%, global mRNA translation was blocked by only 20% suggesting that eIF4E mediated translation initiation does not account for all observed effects of the Mnk inhibitor on TNFα production [34]. This work also established that the heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an ARE binding protein, can be phosphorylated by Mnk1 [34].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, this study demonstrated that although the Mnk inhibitor completely abolished the phosphorylation of eIF4E and suppressed TNFα production by 70%, global mRNA translation was blocked by only 20% suggesting that eIF4E mediated translation initiation does not account for all observed effects of the Mnk inhibitor on TNFα production [34]. This work also established that the heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an ARE binding protein, can be phosphorylated by Mnk1 [34]. Mnk mediated phosphorylation of hnRNPA1 on residues 192 and 301/302/303 was found to reduce the affinity of hnRNPA1 for the ARE in the TNFα mRNA 3’UTR, facilitating the translation of the TNFα mRNA [34].…”

Section: Introductionmentioning

confidence: 99%

“…This work also established that the heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an ARE binding protein, can be phosphorylated by Mnk1 [34]. Mnk mediated phosphorylation of hnRNPA1 on residues 192 and 301/302/303 was found to reduce the affinity of hnRNPA1 for the ARE in the TNFα mRNA 3’UTR, facilitating the translation of the TNFα mRNA [34]. Altogether these results provided evidence for an important role for Mnk1 mediated phosphorylation of hnRNPA1 in promoting TNFα mRNA translation.…”

Section: Introductionmentioning

confidence: 99%

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Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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Section: Rantesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells

et al. 2019

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Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) is a major regulatory node of pro‐inflammatory mediator production by macrophages (MΦs). However, it is still unclear whether such regulation relies on selective translational control by two of the main mTORC1 effectors, the eIF4E‐binding proteins 1 and 2 (4E‐BP1/2). By comparing translational efficiencies of immune‐related transcripts of MΦs from WT and 4E‐BP1/2 double‐KO (DKO) mice, we found that translation of mRNAs encoding the pro‐inflammatory chemokines CCL5 and CXCL10 is controlled by 4E‐BP1/2. Macrophages deficient in 4E‐BP1/2 produced higher levels of CCL5 and CXCL10 upon LPS stimulation, which enhanced chemoattraction of activated T cells. Consistent with this, treatment of WT cells with mTORC1 inhibitors promoted the activation of 4E‐BP1/2 and reduced CCL5 and CXCL10 secretion. In contrast, the phosphorylation status of eIF4E did not affect the synthesis of these chemokines since MΦs derived from mice harboring a non‐phosphorylatable form of the protein produced similar levels of CCL5 and CXCL10 to WT counterparts. These data provide evidence that the mTORC1‐4E‐BP1/2 axis contributes to regulate the production of chemoattractants by MΦs by limiting translation efficiency of Ccl5 and Cxcl10 mRNAs, and suggest that 4E‐BP1/2 act as immunological safeguards by fine‐tuning inflammatory responses in MΦs.

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Tributyltin stimulates synthesis of interferon gamma and tumor necrosis factor alpha in human lymphocytes

Lawrence

Ismail

Jamal

et al. 2018

J of Applied Toxicology

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Tributyltin (TBT) is found in human blood and other tissues and thus is of considerable concern as to its effects on human health. Previous studies have demonstrated that TBT has detrimental effects on immune function. Recently, we found that exposures to TBT caused increased secretion of two important proinflammatory cytokines, tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). Elevation of either of these cytokines has the potential to cause chronic inflammation, which is an important factor in a number of diseases including cancer. The current study examined the mechanism of TBT-induced elevations of TNFα and IFNγ secretion and found that the p38 mitogen-activated protein kinase pathway was essential to the ability of TBT to stimulate secretion. Additionally, this study demonstrated that increased secretion of these cytokines was due to TBT-induced increases in their overall synthesis, rather than simply being due to an increase in the release of already formed proteins. The TBT-induced increases in synthesis were evident within 6 hours of exposure. The p38 mitogen-activated protein kinase pathway is also necessary for the TBT-induced increases in both TNFα and IFNγ synthesis. The role of increased transcription of TNFα and IFNγ mRNA in response to TBT exposures as a possible explanation for the increased synthesis of these cytokines was also examined. It was found that increased mRNA levels did not appear to explain fully the increases in either TNFα or IFNγ synthesis. Thus, TBT is able to increase secretion of two important proinflammatory cytokines by increasing their synthesis.

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The Mnks Are Novel Components in the Control of TNFα Biosynthesis and Phosphorylate and Regulate hnRNP A1

Cited by 188 publications

References 39 publications

Mnk kinases in cytokine signaling and regulation of cytokine responses

Mnk kinases in cytokine signaling and regulation of cytokine responses

Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells

Tributyltin stimulates synthesis of interferon gamma and tumor necrosis factor alpha in human lymphocytes

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