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FXR1 Is an IL-19-Responsive RNA-Binding Protein that Destabilizes Pro-inflammatory Transcripts in Vascular Smooth Muscle Cells

Herman, Allison B. and Vrakas, Christine N. and Ray, Mitali and Kelemen, Sheri E. and Sweredoski, Michael J. and Moradian, Annie and Haines, Dale S. and Autieri, Michael V. (2018) FXR1 Is an IL-19-Responsive RNA-Binding Protein that Destabilizes Pro-inflammatory Transcripts in Vascular Smooth Muscle Cells. Cell Reports, 24 (5). pp. 1176-1189. ISSN 2211-1247. http://resolver.caltech.edu/CaltechAUTHORS:20180731-092548074

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Abstract

This work identifies the fragile-X-related protein (FXR1) as a reciprocal regulator of HuR target transcripts in vascular smooth muscle cells (VSMCs). FXR1 was identified as an HuR-interacting protein by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The HuR-FXR1 interaction is abrogated in RNase-treated extracts, indicating that their association is tethered by mRNAs. FXR1 expression is induced in diseased but not normal arteries. siRNA knockdown of FXR1 increases the abundance and stability of inflammatory mRNAs, while overexpression of FXR1 reduces their abundance and stability. Conditioned media from FXR1 siRNA-treated VSMCs enhance activation of naive VSMCs. RNA EMSA and RIP demonstrate that FXR1 interacts with an ARE and an element in the 3′ UTR of TNFα. FXR1 expression is increased in VSMCs challenged with the anti-inflammatory cytokine IL-19, and FXR1 is required for IL-19 reduction of HuR. This suggests that FXR1 is an anti-inflammation responsive, HuR counter-regulatory protein that reduces abundance of pro-inflammatory transcripts.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.celrep.2018.07.002DOIArticle
ORCID:
AuthorORCID
Sweredoski, Michael J.0000-0003-0878-3831
Additional Information:© 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 7 February 2018, Revised 18 May 2018, Accepted 1 July 2018, Available online 31 July 2018. This work was supported by grants HL141108 and HL117724 from the National Heart, Lung, and Blood Institute of the NIH and grant 17IRG33410646 from the American Heart Association to M.V.A. M.R. and A.B.H. were supported by American Heart Association pre-doctoral fellowships 16PRE31220005 and 17PRE33670798, respectively. A.B.H. was also supported by grant HL137344-01A1 from the National Heart, Lung, and Blood Institute of the NIH. The authors would like to acknowledge the technical expertise of Farah Kako in performing these studies. Author Contributions: A.B.H. performed the majority of the molecular biology experiments; C.N.V. performed cell culture and some molecular biology experiments; M.R. performed cell culture and some molecular biology experiments; S.E.K. performed immunohistochemistry; M.J.S. is the principal investigator of the mass spectrometry lab; A.M. worked in the mass spectrometry lab; D.S.H. interpreted mass spectrometry and other data; M.V.A. designed experiments, interpreted data, performed some western blots, and wrote the manuscript. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIHHL141108
NIHHL117724
American Heart Association17IRG33410646
American Heart Association16PRE31220005
American Heart Association17PRE33670798
NIHHL137344-01A1
Subject Keywords:RNA stability; AU-rich elements; AREs; HuR; FXR1; inflammation; IL-19; anti-inflammatory
Record Number:CaltechAUTHORS:20180731-092548074
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180731-092548074
Official Citation:Allison B. Herman, Christine N. Vrakas, Mitali Ray, Sheri E. Kelemen, Michael J. Sweredoski, Annie Moradian, Dale S. Haines, Michael V. Autieri, FXR1 Is an IL-19-Responsive RNA-Binding Protein that Destabilizes Pro-inflammatory Transcripts in Vascular Smooth Muscle Cells, Cell Reports, Volume 24, Issue 5, 2018, Pages 1176-1189, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2018.07.002. (http://www.sciencedirect.com/science/article/pii/S2211124718310799)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88371
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:31 Jul 2018 16:34
Last Modified:31 Jul 2018 16:34

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