Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response
Authors
Ghari, FatemehQuirke, Anne-Marie
Munro, Shonagh
Kawalkowska, Joanna
Picaud, Sarah
McGouran, Joanna
Subramanian, Venkataraman
Muth, Aaron
Williams, Richard
Kessler, Benedikt
Thompson, Paul R
Fillipakopoulos, Panagis
Knapp, Stefan
Venables, Patrick J.
La Thangue, Nicholas B.
Document Type
Journal ArticlePublication Date
2016-02-05Keywords
BRD4E2F-1
PAD4
cancer
citrullination
immune response
inflammation
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
Metadata
Show full item recordAbstract
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.Source
Sci Adv. 2016 Feb 5;2(2):e1501257. doi: 10.1126/sciadv.1501257. eCollection 2016. Link to article on publisher's websiteDOI
10.1126/sciadv.1501257Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49993PubMed ID
26989780Related Resources
Link to article in PubMedRights
Copyright © 2016, The Authors.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1126/sciadv.1501257