title: RGS2 is a negative regulator of STAT3-mediated Nox1 expression.
abstract: NADPH oxidase 1 (Nox1) is essential for reactive oxygen species production in the innate immune responses mediated by toll-like receptor (TLR), but the mechanism regulating its expression remains uncertain. Here, we find that Nox1 induction is TLR2-dependent, but independent of myeloid differentiation primary response gene 88 (MyD88). We demonstrate the capacity of signal transducer and activator of transcription 3 (STAT3) to activate Nox1's transcription, as well as cooperative regulation by janus kinase 1 and 3 (JAK1 and JAK3). We find that regulator of G-protein signaling 2 (RGS2) inhibits STAT3-mediated Nox1 transcription, and can itself be repressed by TLR2; Nox1 induction upon RGS2 down-regulation is controlled by protein kinase C-η (PKC-η) and phospholipase D2 (PLD2). A GFP-tagged version of RGS2 concentrates in the nucleus; RGS2 additionally directly binds STAT3 to regulate its transcriptional activity through TLR2 stimulation. Cumulatively, these results suggest that TLR2 signaling enhances Nox1 expression through the JAK1/3-STAT3 pathway, and that RGS2, through its regulation by the PKC-η/PLD2 pathway, represses STAT3's transcriptional activation of Nox1.
authors: Department of Biochemistry & Molecular Biology, Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Nam-Gu, Daegu, South Korea.
authors: Hyung-Kyoung
authors: HK
authors: Lee
authors: Dae-Weon
authors: DW
authors: Park
authors: Jun Ho
authors: JH
authors: Bae
authors: Hyung Jun
authors: HJ
authors: Kim
authors: Dong-Gu
authors: DG
authors: Shin
authors: Jong-Seon
authors: JS
authors: Park
authors: Jin-Gu
authors: JG
authors: Lee
authors: Sung Joong
authors: SJ
authors: Lee
authors: Yoe-Sik
authors: YS
authors: Bae
authors: Suk-Hwan
authors: SH
authors: Baek
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D020710:RGS Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D051195:Toll-Like Receptor 2; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; C081975:protein kinase C eta; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D011493:Protein Kinase C; C105606:phospholipase D2; D010739:Phospholipase D