title: 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.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Hyunbin D
authors.initials: HD
authors.lastname: Huh
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Eun A
authors.initials: EA
authors.lastname: Ra
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Taeyun A
authors.initials: TA
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Areum
authors.initials: A
authors.lastname: Park
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Eunhye
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Junhee L
authors.initials: JL
authors.lastname: Choi
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Jang
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, South Korea.|Samsung Genome Institute (SGI), Samsung Medical Center, Seoul, 06351, South Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: National Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 10408, South Korea.
authors.forename: Sungwook
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Boyoun
authors.initials: B
authors.lastname: Park
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D005347:Fibroblasts; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D000067996:RAW 264.7 Cells; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D015850:Interleukin-6; D020930:MAP Kinase Kinase Kinases; D016601:RNA-Binding Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C587672:IL1B protein, mouse; C498144:Rela protein, mouse; C116758:STRAP protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C577686:interleukin-6, mouse