Sam68 is a regulator of Toll-like receptor signaling

• Published in: Cellular & molecular immunology Vol. 14; no. 1; pp. 107 - 117
• Main Authors: Tomalka, Jeffrey A, de Jesus, Tristan J, Ramakrishnan, Parameswaran
• Format: Journal Article
• Language: English
• Published: China Nature Publishing Group 01.01.2017
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Enzyme Activation - drug effects; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Regulation - drug effects; Interleukin-1 - pharmacology; Lipopeptides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; MAP Kinase Signaling System - drug effects; MAPK信号通路; Mice; Mice, Knockout; Models, Biological; NF-kappa B - metabolism; NF-κB; RAW 264.7 Cells; RNA-Binding Proteins - metabolism; Signal Transduction - drug effects; TLR4; Toll-Like Receptors - metabolism; Toll样受体; 丝裂原活化蛋白激酶; 信号调节器; 细胞外信号调节激酶; 诱导表达
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2016.32

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-KB 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.