title: Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein.
abstract: Autophagy is a bulk, nonspecific protein degradation pathway that is involved in the pathogenesis of cancer and neurodegenerative disease. Here, we observed that xanthohumol (XN), a prenylated chalcone present in hops (Humulus lupulus L.) and beer, modulates autophagy. By using XN-immobilized beads, valosin-containing protein (VCP) was identified as a XN-binding protein. VCP has been reported to be an essential protein for autophagosome maturation. Using an in vitro pull down assay, we showed that XN bound directly to the N domain, which is known to mediate cofactor and substrate binding to VCP. These data indicated that XN inhibited the function of VCP, thereby allowing the impairment of autophagosome maturation and resulting in the accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II). This is the first report demonstrating XN as a VCP inhibitor that binds directly to the N domain of VCP. Our finding that XN bound to and inactivated VCP not only reveals the molecular mechanism of XN-modulated autophagy but may also explain how XN exhibits various biological activities that have been reported previously.
authors.affiliation: Faculty of Science and Technology, Department of Biosciences and Informatics, Keio University, Yokohama 223-8522, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sasazawa
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kanagaki
authors.forename: Etsu
authors.initials: E
authors.lastname: Tashiro
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nogawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Muroi
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001515:Beer / Q000032:analysis; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D000074405:Valosin Containing Protein
chemical_list: D001688:Biological Products; D018797:Cell Cycle Proteins; D005419:Flavonoids; D011427:Propiophenones; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C104536:xanthohumol