title: A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents.
abstract: Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage.
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Hata
authors.forename: Jun
authors.initials: J
authors.lastname: Hirayama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kajiho
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hata
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Katada
authors.forename: Makoto
authors.initials: M
authors.lastname: Furutani-Seiki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000477:Alkylating Agents / Q000494:pharmacology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006367:HeLa Cells; D051597:Hippocalcin / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000477:Alkylating Agents; C496691:HPCA protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051597:Hippocalcin; D050880:p300-CBP Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D008239:Lysine