Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response

Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functio
Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.
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Author:Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna McGouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul Richard Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue
URN:urn:nbn:de:hebis:30:3-403239
URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788482
URL:http://advances.sciencemag.org/content/2/2/e1501257
DOI:http://dx.doi.org/10.1126/sciadv.1501257
ISSN:2375-2548
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=26989780
Parent Title (English):Science advances
Publisher:American Association for the Advancement of Science
Place of publication:Washington, DC [u. a.]
Document Type:Article
Language:English
Date of Publication (online):2016/12/12
Date of first Publication:2016/02/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/12/12
Tag:BRD4; E2F-1; PAD4; cancer; citrullination; immune response; inflammation
Volume:2
Issue:2, e1501257
Pagenumber:11
First Page:1
Last Page:10
Note:
2016 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
HeBIS PPN:421459549
Institutes:Pharmazie
Dewey Decimal Classification:540 Chemie und zugeordnete Wissenschaften
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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