title: The unfolded protein response and the phosphorylations of activating transcription factor 2 in the trans-activation of il23a promoter produced by β-glucans.
abstract: Current views on the control of IL-23 production focus on the regulation of il23a, the gene encoding IL-23 p19, by NF-κB in combination with other transcription factors. C/EBP homologous protein (CHOP), X2-Box-binding protein 1 (XBP1), activator protein 1 (AP1), SMAD, CCAAT/enhancer-binding protein (C/EBPβ), and cAMP-response element-binding protein (CREB) have been involved in response to LPS, but no data are available regarding the mechanism triggered by the fungal mimic and β-glucan-containing stimulus zymosan, which produces IL-23 and to a low extent the related cytokine IL-12 p70. Zymosan induced the mobilization of CHOP from the nuclear fractions to phagocytic vesicles. Hypha-forming Candida also induced the nuclear disappearance of CHOP. Assay of transcription factor binding to the il23a promoter showed an increase of Thr(P)-71-Thr(P)-69-activating transcription factor 2 (ATF2) binding in response to zymosan. PKC and PKA/mitogen- and stress-activated kinase inhibitors down-regulated Thr(P)-71-ATF2 binding to the il23a promoter and il23a mRNA expression. Consistent with the current concept of complementary phosphorylations on N-terminal Thr-71 and Thr-69 of ATF2 by ERK and p38 MAPK, MEK, and p38 MAPK inhibitors blunted Thr(P)-69-ATF2 binding. Knockdown of atf2 mRNA with siRNA correlated with inhibition of il23a mRNA, but it did not affect the expression of il12/23b and il10 mRNA. These data indicate the following: (i) zymosan decreases nuclear proapoptotic CHOP, most likely by promoting its accumulation in phagocytic vesicles; (ii) zymosan-induced il23a mRNA expression is best explained through coordinated κB- and ATF2-dependent transcription; and (iii) il23a expression relies on complementary phosphorylation of ATF2 on Thr-69 and Thr-71 dependent on PKC and MAPK activities.
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valladolid, 47005-Valladolid.
authors: Mario
authors: M
authors: Rodríguez
authors: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003-Valladolid.
authors: Esther
authors: E
authors: Domingo
authors: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003-Valladolid.
authors: Sara
authors: S
authors: Alonso
authors: Division of Hematology, Hospital Universitario Rio Hortega, 47012-Valladolid, and.
authors: Javier García
authors: JG
authors: Frade
authors: Division of Microbiology, Hospital Universitario Rio Hortega, 47012-Valladolid, Spain.
authors: José
authors: J
authors: Eiros
authors: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003-Valladolid,. Electronic address: mscres@ibgm.uva.es.
authors: Mariano Sánchez
authors: MS
authors: Crespo
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valladolid, 47005-Valladolid.
authors: Nieves
authors: N
authors: Fernández
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053760:Interleukin-23 Subunit p19 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects* / Q000502:physiology; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000502:physiology; D015054:Zymosan / Q000494:pharmacology*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C508840:IL23A protein, human; D053760:Interleukin-23 Subunit p19; D015054:Zymosan; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ATF2; Cyclic AMP (cAMP); Dendritic Cell; ER Stress; Fungal Infection; IL-23; Prostaglandin E2; Unfolded Protein Response (UPR); cAMP-response Element-binding Protein (CREB); β-Glucans