Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages.
Cot/tpl2 is the only MAP3K that activates MKK1/2-Erk1/2 in Toll-like receptor-activated macrophages. Here we show that Cot/tpl2 regulates RSK, S6 ribosomal protein, and 4E-BP phosphorylation after stimulation of bone marrow-derived macrophages with lipopolysaccharide (LPS), poly I:C, or zymosan. The dissociation of the 4E-BP-eIF4E complex, a key event in the cap-dependent mRNA translation initiation, is dramatically reduced in LPS-stimulated Cot/tpl2-knockout (KO) macrophages versus LPS-stimulated wild-type (Wt) macrophages. Accordingly, after LPS activation, increased cap-dependent translation is observed in Wt macrophages but not in Cot/tpl2 KO macrophages. In agreement with these data, Cot/tpl2 increases the polysomal recruitment of the 5´ TOP eEF1α and eEF2 mRNAs, as well as of inflammatory mediator gene-encoding mRNAs, such as tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and KC in LPS-stimulated macrophages. In addition, Cot/tpl2 deficiency also reduces total TNFα, IL-6, and KC mRNA expression in LPS-stimulated macrophages, which is concomitant with a decrease in their mRNA half-lives. Macrophages require rapid fine control of translation to provide an accurate and not self-damaging response to host infection, and our data show that Cot/tpl2 controls inflammatory mediator gene-encoding mRNA translation in Toll-like receptor-activated macrophages.
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, 28029 Madrid, Spain.
Marta
M
López-Pelaéz
Stefano
S
Fumagalli
Carlos
C
Sanz
Clara
C
Herrero
Susana
S
Guerra
Margarita
M
Fernandez
Susana
S
Alemany
D000818:Animals; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D060588:LIM Domain Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
C441450:Crip3 protein, mouse; C519509:Crtc1 protein, mouse; D060588:LIM Domain Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048369:MAP Kinase Kinase 1