Abstract
The WD40-repeat protein serine/threonine kinase receptor-associated protein (STRAP) is involved in the regulation of several biological processes, including cell proliferation and apoptosis, in response to various stresses. Here, we show that STRAP is a new scaffold protein that functions in Toll-like receptor (TLR)-mediated immune responses. STRAP specifically binds transforming growth factor β-activated kinase 1 (TAK1) and IκB kinase alpha (IKKα) along with nuclear factor-κB (NF-κB) subunit p65, leading to enhanced association between TAK1, IKKα, and p65, and subsequent facilitation of p65 phosphorylation and nuclear translocation. Consequently, the depletion of STRAP severely impairs interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-1β production, whereas its overexpression causes a significant increase in the secretion of these pro-inflammatory cytokines by TLR2 or TLR4 agonist-stimulated macrophages. Notably, STRAP translocates to the nucleus and subsequently binds to NF-κB at later times after lipopolysaccharide (LPS) stimulation, resulting in prolonged IL-6 mRNA production. Moreover, the C-terminal region of STRAP is essential for its functional activity in facilitating IL-6 production. Collectively, these observations suggest that STRAP acts as a scaffold protein that positively contributes to innate host defenses against pathogen infections.
Highlights
Toll-like receptors (TLRs) are involved in the detection of conserved pathogen components such as pattern-recognition receptors and are important for innate immune responses[1,2]
Serine-threonine kinase receptor-associated protein (STRAP) plays a role in regulating the transforming growth factor (TGF)-βsignaling pathway, which is involved in cross-talk with the nuclear factor-κB (NF-κB) signaling pathway[6,16]
We report that STRAP serves as a scaffold protein and positively regulates the TLR-mediated signaling pathway
Summary
Toll-like receptors (TLRs) are involved in the detection of conserved pathogen components such as pattern-recognition receptors and are important for innate immune responses[1,2]. The pro-inflammatory pathway through TLR2 or TLR4 signaling is dependent on the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6), transforming growth factor β-activated kinase 1 (TAK1), and IκB kinase (IKK), which are critical adaptors for the activation and nuclear translocation of nuclear factor-κB (NF-κB), thereby leading to the transcriptional induction of inflammatory genes. The C-terminal region of STRAP, is necessary to enhance p65 phosphorylation, its interaction with TAK1, and subsequently the production of pro-inflammatory cytokines. Overall, these findings suggest the existence of a new scaffold protein that positively and continually regulates pro-inflammatory cytokine gene expression during pathogen infection
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