STRAP positively regulates TLR3-triggered signaling pathway

Cell Immunol. 2017 Aug;318:55-60. doi: 10.1016/j.cellimm.2017.06.005. Epub 2017 Jun 19.

Abstract

Toll-like receptor (TLR) signaling drives the innate immune response by activating nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF). We have previously shown that STRAP interacts with TAK1 and IKKα along with NF-κB subunit p65, leading to the activation of pro-inflammatory cytokines. However, the roles of STRAP in TRIF/TBK1-mediated TLR3 activation and the subsequent type I interferon (IFN) production are not fully elucidated. Here, we demonstrate that STRAP acts as a scaffold protein in TLR3-triggered signaling. STRAP strongly interacts with TBK1 and IRF3, which enhances IFN-β production. As a consequence, STRAP knockdown reduces the level of both pro-inflammatory cytokine and IFN in TLR3 agonist-stimulated macrophages, whereas its overexpression significantly enhances production of these cytokines. Furthermore, the C-terminus of STRAP is essential for its functional activity in TLR3-mediated IL-6 and IFN-β production. These data suggest that STRAP is a positive regulator of the TLR3-meditated NF-κB and IRF signaling pathway.

Keywords: Cytokine; STRAP; Scaffold protein; Signal transduction; TLR3.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cytokines / metabolism
  • HEK293 Cells
  • Humans
  • Inflammation / immunology*
  • Interferon Regulatory Factor-3 / metabolism
  • Macrophages / immunology*
  • Mice
  • NF-kappa B / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • RAW 264.7 Cells
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins
  • Signal Transduction
  • Toll-Like Receptor 3 / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • NF-kappa B
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • STRAP protein, mouse
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases