STRAP Acts as a Scaffolding Protein in Controlling the TLR2/4 Signaling Pathway

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.

Altered mitochondrial metabolism in the insulin‐resistant heart

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Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms

“…Despite the clinical implications of lipid accumulation in the heart (Poirier et al, 2006; He et al, 2017; Anstee et al, 2018; De Coster et al, 2018), the underlying molecular mechanisms are poorly understood. A major limitation could be due to the complexity associated with the involvement of multiple signaling pathways which include: (1) direct modulation of ion channel function by FFAs, and (2) FFA activation of the toll-like receptor (TLR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) leading to secretion of pro-inflammatory cytokines (Huh et al, 2016) and subsequent cardiac electrical remodeling. Previous reports have demonstrated that FFAs increase inflammation (Lundman et al, 2007), while genetic knockdown of TLR is protective in mice fed a high-fat diet rich in palmitate (Davis et al, 2008).…”

Hiding in Plain Sight: The Globally Distributed Bacterial Candidate Phylum PAUC34f

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