title: A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1.
abstract: In the context of the human airway, interleukin-17A (IL-17A) signaling is associated with severe inflammation, as well as protection against pathogenic infection, particularly at mucosal surfaces such as the airway. The intracellular molecule Act1 has been demonstrated to be an essential mediator of IL-17A signaling. In the cytoplasm, it serves as an adaptor protein, binding to both the intracellular domain of the IL-17 receptor as well as members of the canonical nuclear factor kappa B (NF-κB) pathway. It also has enzymatic activity, and serves as an E3 ubiquitin ligase. In the context of airway epithelial cells, we demonstrate for the first time that Act1 is also present in the nucleus, especially after IL-17A stimulation. Ectopic Act1 expression can also increase the nuclear localization of Act1. Act1 can up-regulate the expression and promoter activity of a subset of IL-17A target genes in the absence of IL-17A signaling in a manner that is dependent on its N- and C-terminal domains, but is NF-κB independent. Finally, we show that nuclear Act1 can bind to both distal and proximal promoter regions of DEFB4, one of the IL-17A responsive genes. This transcriptional regulatory activity represents a novel function for Act1. Taken together, this is the first report to describe a non-adaptor function of Act1 by directly binding to the promoter region of IL-17A responsive genes and directly regulate their transcription.
authors.affiliation: The Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Sharlene
authors.initials: S
authors.lastname: Velichko
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona, Tucson, Arizona, 85721, United States of America.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona, Tucson, Arizona, 85721, United States of America.
authors.forename: Lingxiang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: The Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Johnathon David
authors.initials: JD
authors.lastname: Anderson
authors.affiliation: The Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Reen
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona, Tucson, Arizona, 85721, United States of America.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C106641:DEFB4A protein, human; C508717:IL17A protein, human; D020381:Interleukin-17; D016328:NF-kappa B; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D023083:beta-Defensins