S6K1 Negatively Regulates TAK1 Activity in the Toll-Like Receptor Signaling Pathway

Abstract

dTransforming growth factor ␤ (TGF-␤)-activated kinase 1 (TAK1) is a key regulator in the signals transduced by proinflammatory cytokines and Toll-like receptors (TLRs). The regulatory mechanism of TAK1 in response to various tissue types and stimuli remains incompletely understood. Here, we show that ribosomal S6 kinase 1 (S6K1) negatively regulates TLR-mediated signals by inhibiting TAK1 activity. S6K1 overexpression causes a marked reduction in NF-B and AP-1 activity induced by stimulation of TLR2 or TLR4. In contrast, S6K1؊/؊ and S6K1 knockdown cells display enhanced production of inflammatory cytokines. Moreover, S6K1؊/؊ mice exhibit decreased survival in response to challenge with lipopolysaccharide (LPS). We found that S6K1 inhibits TAK1 kinase activity by interfering with the interaction between TAK1 and TAB1, which is a key regulator protein for TAK1 catalytic function. Upon stimulation with TLR ligands, S6K1 deficiency causes a marked increase in TAK1 kinase activity that in turn induces a substantial enhancement of NF-B-dependent gene expression, indicating that S6K1 is negatively involved in the TLR signaling pathway by the inhibition of TAK1 activity. Our findings contribute to understanding the molecular pathogenesis of the impaired immune responses seen in type 2 diabetes, where S6K1 plays a key role both in driving insulin resistance and modulating TLR signaling.T ransforming growth factor ␤-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) family (1). TAK1 is essential for the production of tumor necrosis factor (TNF-␣) and other inflammatory mediators by activating several MAPKs, such as p38␣ MAPK, Jun N-terminal protein kinases 1 and 2 (JNK1 and JNK2), and extracellular signal-regulated kinases 1 and 2 (ERK1/2). TAK1 also plays a key regulatory role in several cytokine-mediated innate immunity signal transduction cascades, including interleukin-1 (IL-1) and the downstream signaling of Toll-like receptors (TLRs) and NOD1/2 (2, 3). In these pathways, various proinflammatory cytokines and TLR agonists trigger TAK1 activity, leading to its autophosphorylation and subsequent recruitment to the IB kinase (IKK) complex, ultimately resulting in the activation of the transcription factor NF-B and the upregulation of genes encoding proinflammatory cytokines, chemokines, adhesion molecules, and proteolytic enzymes.Several binding partners of TAK1, including TAK1-binding protein 1 (TAB1), TAB2, and TAB3, have been implicated in the regulation of TAK1 activity in response to various stimuli (1, 4). Previous reports demonstrated that the native forms of TAK1 comprise a catalytic kinase subunit in complex with the regulatory subunit TAB1 and either of two homologous proteins, TAB2 and TAB3 (2, 5, 6). Importantly, it has been reported that TAB1 might play a key role in the regulation of the TAK1 complex (7,8). Studies with TAB1-deficient mouse embryonic fibroblasts (TAB1 Ϫ/Ϫ MEFs) demonstrated that TAB1 is able to recruit p38␣ MAPK to the TAK1 complex f...

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

“…Among the novel immune-related MS, susceptibility candidates within or immediately adjacent to these non-overlapping regions are: MAP3K14 , which encodes NF-κB inducing kinase (NIK), a central component of non-canonical NF-κB activation; RELA , which encodes the NF-κB p65 subunit; UBASH3B , which cooperates with INPP5D to negatively regulate NF-κB signaling downstream of Fc receptor activation; 16 NCOA2 , a dose-dependent regulator of NF-κB activity; 17 TNFAIP8 , a negative regulator of NF-κB activation that maintains immune homeostasis; 18 KAT5 , which acts as a molecular bridge between RELA activation and NF-κB target genes; 19 CSF2RB , a mediator of cytokine-induced JAK/STAT signaling cascades; 20 STIM2 , which regulates autoimmune effector functions of Th1 and T helper type 17 (Th17) cells; 21 TXK , a Th1 cell-specific transcription factor; 22 DPP4 (CD26), a T-cell activation marker implicated in autoimmune pathology and highly expressed on Th17 cells; 23 CADM1 , a cell adhesion molecule that promotes cell-mediated cytotoxicity; 24 DAP , a positive regulator of IFN-γ mediated cell-death 25 and RGCC , a regulator of T-cell-mediated apoptosis. 26 …”

“…Knockdown of this inhibition results in enhanced production of inflammatory cytokines. 19 Cytokine response to NF-κB signaling is dependent on the profile of subunit activation, 52 and is subject to coordinated regulation by other signaling pathways.…”

Toll signal transduction pathway in bivalves: Complete cds of intermediate elements and related gene transcription levels in hemocytes of immune stimulated Mytilus galloprovincialis

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High Dietary Selenium Intake Alters Lipid Metabolism and Protein Synthesis in Liver and Muscle of Pigs

“…Alterations of these factors were associated with expressions of 12 selenoproteins (1,3,5,9,18,19). However, to the best of our knowledge, there was no information on effects of dietary selenium, in particular high selenium intake, on body protein metabolism, although protein synthesis was reported to negatively regulate insulin sensitivity (20,21) and a high protein diet inhibited the development of type 2 diabetes (22). Mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (P70), ribosomal protein S6 (S6), factor 4E binding protein 1 (4EBP1), and eukaryotic translation initiation factor 4E (EIF4E) are key factors involved in the protein synthesis pathway (23)(24)(25)(26)(27).…”