title: Brazilin selectively disrupts proximal IL-1 receptor signaling complex formation by targeting an IKK-upstream signaling components.
abstract: The ligation of interleukin-1 receptor (IL-1R) or tumor necrosis factor receptor 1 (TNFR1) induces the recruitment of adaptor proteins and their concomitant ubiquitination to the proximal receptor signaling complex, respectively. Such are upstream signaling events of IKK that play essential roles in NF-κB activation. Thus, the discovery of a substance that would modulate the recruitment of key proximal signaling elements at the upstream level of IKK has been impending in this field of study. Here, we propose that brazilin, an active compound of Caesalpinia sappan L. (Leguminosae), is a potent NF-κB inhibitor that selectively disrupts the formation of the upstream IL-1R signaling complex. Analysis of upstream signaling events revealed that brazilin markedly abolished the IL-1β-induced polyubiquitination of IRAK1 and its interaction with IKK-γ counterpart. Notably, pretreatment of brazilin drastically interfered the recruitment of the receptor-proximal signaling components including IRAK1/4 and TRAF6 onto MyD88 in IL-1R-triggerd NF-κB activation. Interestingly, brazilin did not affect the TNF-induced RIP1 ubiquitination and the recruitment of RIP1 and TRAF2 to TNFR1, suggesting that brazilin is effective in selectively suppressing the proximal signaling complex formation of IL-1R, but not that of TNFR1. Moreover, our findings suggest that such a disruption of IL-1R-proximal complex formation by brazilin is not mediated by affecting the heterodimerization of IL-1R and IL-1RAcP. Taken together, the results suggest that the anti-IKK activity of brazilin is induced by targeting IKK upstream signaling components and subsequently disrupting proximal IL-1 receptor signaling complex formation.
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Juhee
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Department of Physics, Amherst College, Amherst, MA 01002-5000, USA.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Kyeong Ah
authors.initials: KA
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Byun
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Hyunji
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Kidong
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Seok
authors.affiliation: Department of Biology, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Biology, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea.
authors.forename: Man-Deuk
authors.initials: MD
authors.lastname: Han
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Seong Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
authors.forename: Jang Hee
authors.initials: JH
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea. Electronic address: gmhur@cnu.ac.kr.
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D029911:Caesalpinia / Q000737:chemistry; D020834:Ethnopharmacology; D017930:Genes, Reporter / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D056910:Republic of Korea; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D014934:Wood / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D020672:I-kappa B Proteins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; C495345:TLR4 protein, human; C439524:TNF protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase; C044362:brazilin
keywords: Brazilin; IKK; IL-1 receptor signaling complex; Nuclear factor-κB; Protein interaction; Ubiquitination