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 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 QuirkeORCiD, Shonagh Munro, Joanna KawalkowskaORCiD, Sarah Picaud, Joanna McGouran, Venkataraman Subramanian, Aaron MuthORCiD, Richard WilliamsORCiD, Benedikt Kessler, Paul Richard Thompson, Panagis Fillipakopoulos, Stefan KnappORCiD, Patrick J. Venables, Nicholas B. La Thangue
Pubmed Id:
Parent Title (English):Science advances
Publisher:American Association for the Advancement of Science
Place of publication:Washington, DC [u. a.]
Document Type:Article
Date of Publication (online):2016/12/05
Date of first Publication:2016/02/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/12/05
Tag:BRD4; E2F-1; PAD4; cancer; citrullination; immune response; inflammation
Issue:2, e1501257
Page Number:11
First Page:1
Last Page:10
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).
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0