title: The adenovirus E4orf4 protein targets PP2A to the ACF chromatin-remodeling factor and induces cell death through regulation of SNF2h-containing complexes.
abstract: The adenovirus E4 open-reading-frame 4 (E4orf4) protein regulates the progression of viral infection and when expressed individually it induces non-classical apoptosis in transformed cells. Here we show that E4orf4 associates with the ATP-dependent chromatin-remodeling factor ACF that consists of a sucrose non fermenting-2h (SNF2h) ATPase and an Acf1 regulatory subunit. Furthermore, E4orf4 targets protein phosphatase 2A (PP2A) to this complex and to chromatin. Obstruction of SNF2h activity inhibits E4orf4-induced cell death, whereas knockdown of Acf1 results in enhanced E4orf4-induced toxicity in both mammalian and yeast cells, and Acf1 overexpression inhibits E4orf4's ability to downregulate early adenovirus gene expression in the context of viral infection. Knockdown of the Acf1 homolog, WSTF, inhibits E4orf4-induced cell death. Based on these results we suggest that the E4orf4-PP2A complex inhibits ACF and facilitates enhanced chromatin-remodeling activities of other SNF2h-containing complexes, such as WSTF-SNF2h. The resulting switch in chromatin remodeling determines life versus death decisions and contributes to E4orf4 functions during adenovirus infection.
authors.affiliation: Department of Molecular Microbiology, Faculty of Medicine, Technion - Israel Institute of Technology, Bat Galim, Haifa 31096, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Brestovitsky
authors.forename: Rakefet
authors.initials: R
authors.lastname: Sharf
authors.forename: Karin
authors.initials: K
authors.lastname: Mittelman
authors.forename: Tamar
authors.initials: T
authors.lastname: Kleinberger
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D017209:Apoptosis; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D015536:Down-Regulation; D005656:Fungal Proteins / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006801:Humans; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015003:Yeasts / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000251:Adenosine Triphosphatases; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D005656:Fungal Proteins; D054648:Protein Phosphatase 2; D014157:Transcription Factors; D014764:Viral Proteins; C492319:BAZ1A protein, human; D000092468:Bromodomain Containing Proteins; C116750:BAZ1B protein, human; C121517:E4orf4 protein, adenovirus; C409462:SMARCA5 protein, human