A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1
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...
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2016
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ndltd-arizona.edu-oai-arizona.openrepository.com-10150-6219472017-01-15T03:00:39Z A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 Velichko, Sharlene Zhou, Xu Zhu, Lingxiang Anderson, Johnathon David Wu, Reen Chen, Yin Univ Arizona, Sch Pharm, Dept Pharmacol & Toxicol 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-kappa B) 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-kappa B 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. 2016-10-10 Article A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 2016, 11 (10):e0163323 PLOS ONE 1932-6203 27723765 10.1371/journal.pone.0163323 http://hdl.handle.net/10150/621947 http://arizona.openrepository.com/arizona/handle/10150/621947 PLOS ONE en http://dx.plos.org/10.1371/journal.pone.0163323 © 2016 Velichko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License. PUBLIC LIBRARY SCIENCE |
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en |
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description |
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-kappa B) 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-kappa B 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. |
author2 |
Univ Arizona, Sch Pharm, Dept Pharmacol & Toxicol |
author_facet |
Univ Arizona, Sch Pharm, Dept Pharmacol & Toxicol Velichko, Sharlene Zhou, Xu Zhu, Lingxiang Anderson, Johnathon David Wu, Reen Chen, Yin |
author |
Velichko, Sharlene Zhou, Xu Zhu, Lingxiang Anderson, Johnathon David Wu, Reen Chen, Yin |
spellingShingle |
Velichko, Sharlene Zhou, Xu Zhu, Lingxiang Anderson, Johnathon David Wu, Reen Chen, Yin A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 |
author_sort |
Velichko, Sharlene |
title |
A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 |
title_short |
A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 |
title_full |
A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 |
title_fullStr |
A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 |
title_full_unstemmed |
A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1 |
title_sort |
novel nuclear function for the interleukin-17 signaling adaptor protein act1 |
publisher |
PUBLIC LIBRARY SCIENCE |
publishDate |
2016 |
url |
http://hdl.handle.net/10150/621947 http://arizona.openrepository.com/arizona/handle/10150/621947 |
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