Keap1-independent regulation of Nrf2 activity by protein acetylation and a BET bromodomain protein

• Verfasst von: Chatterjee, Nirmalya [VerfasserIn]
• Verfasst von: Boutros, Michael [VerfasserIn]
• Titel: Keap1-independent regulation of Nrf2 activity by protein acetylation and a BET bromodomain protein
• Verf.angabe: Nirmalya Chatterjee, Min Tian, Kerstin Spirohn, Michael Boutros, Dirk Bohmann
• E-Jahr: 2016
• Jahr: May 27, 2016
• Umfang: 20$p12(2016,5) Artikel-Nummer e1006072, 20 Seiten S.
• Fussnoten: Gesehen am 29.04.2019
• Titel Quelle: Enthalten in: Public Library of SciencePLoS Genetics
• Ort Quelle: San Francisco, Calif. : Public Library of Science, 2005
• Jahr Quelle: 2016
• Band/Heft Quelle: 12(2016), 5
• ISSN Quelle: 1553-7404
• DOI: doi:10.1371/journal.pgen.1006072
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Acetylation
• Sach-SW: Drosophila melanogaster
• Sach-SW: Drug therapy
• Sach-SW: Gene expression
• Sach-SW: Gene regulation
• Sach-SW: Oxidative stress
• Sach-SW: RNA interference
• Sach-SW: Transcription factors
• K10plus-PPN: 1663738629

Abstract

Mammalian BET proteins comprise a family of bromodomain-containing epigenetic regulators with complex functions in chromatin organization and gene regulation. We identified the sole member of the BET protein family in Drosophila, Fs(1)h, as an inhibitor of the stress responsive transcription factor CncC, the fly ortholog of Nrf2. Fs(1)h physically interacts with CncC in a manner that requires the function of its bromodomains and the acetylation of CncC. Treatment of cultured Drosophila cells or adult flies with fs(1)h RNAi or with the BET protein inhibitor JQ1 de-represses CncC transcriptional activity and engages protective gene expression programs. The mechanism by which Fs(1)h inhibits CncC function is distinct from the canonical mechanism that stimulates Nrf2 function by abrogating Keap1-dependent proteasomal degradation. Consistent with the independent modes of CncC regulation by Keap1 and Fs(1)h, combinations of drugs that can specifically target these pathways cause a strong synergistic and specific activation of protective CncC- dependent gene expression and boosts oxidative stress resistance. This synergism might be exploitable for the design of combinatorial therapies to target diseases associated with oxidative stress or inflammation.