MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL

Landon, Ari L.; Muniandy, Parameswary A.; Shetty, Amol C.; Lehrmann, Elin; Vallar, Laurent; Houng, Simone; Zhang, Yongqing; Dai, Bojie; Peroutka, Raymond J.; Mazan-Mamczarz, Krystyna; Steinhardt, James J.; Mahurkar, Anup; Becker, Kevin G.; Borden, Katherine L. B.; Gartenhaus, Ronald B.

doi:10.1038/ncomms6413

Cited by 79 publications

(95 citation statements)

References 45 publications

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“…S5). Further supporting a role of Mnk2 in the resynthesis of IκBα, we found that treatment of Brd4-deficient BMDMs with the Mnk2 inhibitor cercosporamide (27), which inhibited phosphorylation of eIF4E (Fig. S9A), suppressed LPS-induced IκBα resynthesis accompanied by increased nuclear RelA (Fig.…”

Section: Discussionsupporting

confidence: 61%

“…Mnk2 and Mnk1 are protein kinases that are directly phosphorylated and activated by ERK or p38 MAP kinases and have been implicated in the regulation of protein synthesis through their phosphorylation of eIF4E at S209 (10,27,28). When we examined the activation of Mnk2 in LPS-treated BMDMs, we found that the cellular levels of Mnk2 decreased with the LPS stimulation in WT BMDMs (Fig.…”

Section: Resultsmentioning

confidence: 91%

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Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Bao

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/ threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.T he inducible transcription factor NF-κB plays a key role in regulating the inflammatory and immune responses in mammals (1, 2). The prototypical NF-κB complex, the heterodimer of p50 and RelA, is sequestered in the cytoplasm by its assembly with its inhibitor IκBα (1, 2). Upon stimulation, IκB kinase complex is activated and phosphorylates IκBα, leading to the degradation of IκBα, the nuclear translocation of NF-κB complex, and the activation of NF-κB target genes (1-3). Importantly, one of NF-κB target genes is its inhibitor, IκBα. The resynthesized IκBα enters the nucleus, where it removes the NF-κB from the DNA and terminates activated NF-κB (1, 2, 4). The resynthesis of IκBα therefore creates a negative feedback regulation of NF-κB signaling, preventing sustained NF-κB activation and prolonged inflammatory response.In addition to the negative feedback regulation from resynthesized IκBα, the NF-κB-mediated inflammatory response is subjected to many layers of regulation, including transcriptional, translational, and posttranslational regulation (5-8). Recent studies demonstrate that selective translational control of gene expression plays an important regulatory role in the inflammatory response (7, 9). The eukaryotic translation initiation factor eIF4E has been shown to be the node of the translational control of immune response via the mTOR signaling pathway or the MAPK-Mnk1-Mnk2-eIF4E pathway (9). Upon LPS stimulation, eIF4E can be activated via its phosphorylation at S209 by Mnk1/2 (10). The phosphorylated eIF4E then activates the translation of mRNA of inflammatory genes, including IRF8 (11, 12). Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of e...

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Section: Discussionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 91%

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Bao

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Two recent studies identified increased expression/phosphorylation of specific mRNA translation initiation factors (eIFs), eIF4B and eIF4E, in diffuse large B-cell lymphoma. 8,9 In CLL, stimulation of malignant cells by CD40L-expressing stromal cells increased global mRNA translation and formation of the eIF4F complex, which binds the 59CAP of mRNAs and enhances mRNA translation. 10 Previous comparisons of geneexpression profiling (GEP) and proteomic analysis revealed differences in the transcriptomic and proteomic response after sIgM stimulation of CLL cells, pointing to posttranscriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation

Yeomans

Thirdborough

Valle-Argos

et al. 2016

Blood

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“…In adult cardiocytes, overexpression of wild-type MNK1 stimulated translation of mRNA, regardless of the presence of secondary structure in the 5Ј-UTR (49). In diffuse large B-cell lymphoma cells, modulation of MNK1/2 activity differentially affects mRNAs that utilize eIF4E1-versus eIF4E3-driven translation on the basis of a 5Ј-UTR motif (50). In breast carcinoma (MDA-MB-435) cells, ␣6␤4-integrin-dependent activation of MNK stimulates translation of VEGF mRNA, which contains a long, highly structured 5Ј-UTR, but not GAPDH mRNA, which contains a short 5Ј-UTR with little secondary structure (35).…”

mentioning

confidence: 99%

Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5′-Terminal Cap and Hairpin

Korneeva

Song

Gram

et al. 2016

Journal of Biological Chemistry

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The MAPK-interacting kinases 1 and 2 (MNK1 and MNK2) are activated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) or p38 in response to cellular stress and extracellular stimuli that include growth factors, cytokines, and hormones. Modulation of MNK activity affects translation of mRNAs involved in the cell cycle, cancer progression, and cell survival. However, the mechanism by which MNK selectively affects translation of these mRNAs is not understood. MNK binds eukaryotic translation initiation factor 4G (eIF4G) and phosphorylates the cap-binding protein eIF4E. Using a cell-free translation system from rabbit reticulocytes programmed with mRNAs containing different 5-ends, we show that an MNK inhibitor, CGP57380, affects translation of only those mRNAs that contain both a cap and a hairpin in the 5-UTR. Similarly, a C-terminal fragment of human eIF4G-1, eIF4G(1357-1600), which prevents binding of MNK to intact eIF4G, reduces eIF4E phosphorylation and inhibits translation of only capped and hairpin-containing mRNAs. Analysis of proteins bound to m 7 GTP-Sepharose reveals that both CGP and eIF4G(1357-1600) decrease binding of eIF4E to eIF4G. These data suggest that MNK stimulates translation only of mRNAs containing both a cap and 5-terminal RNA duplex via eIF4E phosphorylation, thereby enhancing the coupled cap-binding and RNA-unwinding activities of eIF4F.The rate of translational initiation in eukaryotic cells depends on both cis-acting features of individual mRNAs, such as the cap, poly(A) tract, and untranslated regions (UTRs), and trans-acting components, such as initiation factors, protein kinases, and microRNAs (1-3). The recruitment of capped mRNAs to 48S initiation complexes involves several discrete steps that include cap recognition by eukaryotic translation initiation factor 4E (eIF4E), 3 mRNA binding by eIF4G, ATP-dependent unwinding of 5Ј-terminal secondary structure by the helicase eIF4A in concert with eIF4B and eIF4H, recognition of the 3Ј-terminal poly(A) tract by poly(A)-binding protein (PABP), and binding of eIF4G to the 40S ribosomal subunit through eIF3. Both the primary and secondary structure of the 5Ј-UTR are capable of modulating translational efficiency (4, 5). mRNAs containing short 5Ј-UTRs with little secondary structure or terminal oligopyrimidine tracts are more efficiently translated under normal conditions with a limited level of eIF4E. Translational efficiency is diminished in mRNAs containing long, GϩC-rich, and highly structured 5Ј-UTRs because of the necessity for energy-dependent unwinding prior to start codon recognition (6). Translation of these mRNAs requires high levels of eIF4F, the complex of eIF4E, eIF4A, and eIF4G (3, 7). The availability of eIF4E to enter the eIF4F complex is regulated by the PI3K/Akt/mTOR signaling cascade; eIF4E is sequestered by binding to the 4E-BPs, but activation of the mTOR kinase causes phosphorylation of the 4E-BPs and release of eIF4E (8, 9). The activity of eIF4E can be also regulated by phosphorylation via the mitogen-activat...

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MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL

Cited by 79 publications

References 45 publications

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation

Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5′-Terminal Cap and Hairpin

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