title: Sam68 is a regulator of Toll-like receptor signaling.
abstract: Recognition of pathogens by Toll-like receptors (TLR) activate multiple signaling cascades and expression of genes tailored to mount a primary immune response, inflammation, cell survival and apoptosis. Although TLR-induced activation of pathways, such as nuclear factor kappaB (NF-κB) and mitogen-activated protein kinases (MAPK), has been well studied, molecular entities controlling quantitative regulation of these pathways during an immune response remain poorly defined. We identified Sam68 as a novel regulator of TLR-induced NF-κB and MAPK activation. We found that TLR2 and TLR3 are totally dependent, whereas TLR4 is only partially dependent on Sam68 to induce the activation of NF-κB c-Rel. Absence of Sam68 greatly decreased TLR2- and TLR3-induced NF-κB p65 activation, whereas TLR4-induced p65 activation in a Sam68-independent manner. In contrast, Sam68 appeared to be a negative regulator of MAPK pathways because absence of Sam68 enhanced TLR2-induced activation of extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK). Interestingly, TLR2- and TLR3-induced gene expression showed a differential requirement of Sam68. Absence of Sam68 impaired TLR2-induced gene expression, suggesting that Sam68 has a critical role in myeloid differentiation primary response gene 88-dependent TLR2 signaling. TLR3-induced gene expression that utilize Toll/Interleukin-1 receptor-domain-containing adapter-inducing beta interferon pathway, depend only partially on Sam68. Our findings suggest that Sam68 may function as an immune rheostat that balances the activation of NF-κB p65 and c-Rel, as well as MAPK, revealing a potential novel target to manipulate TLR signaling.
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Tomalka
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: de Jesus
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Ramakrishnan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology; D055666:Lipopeptides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D000067996:RAW 264.7 Cells; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007375:Interleukin-1; C513253:Khdrbs1 protein, mouse; D055666:Lipopeptides; D016328:NF-kappa B; C508075:Pam(3)CSK(4) peptide; D016601:RNA-Binding Proteins; D051193:Toll-Like Receptors