Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein

Yukiko Sasazawa, Shuhei Kanagaki, Etsu Tashiro, Toshihiko Nogawa, Makoto Muroi, Yasumitsu Kondoh, Hiroyuki Osada, Masaya Imoto

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)892-900
Number of pages9
JournalACS Chemical Biology
Volume7
Issue number5
DOIs
Publication statusPublished - 2012 May 18

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Autophagy
Humulus
Neurodegenerative diseases
Chalcone
Autophagosomes
xanthohumol
CDC48 protein
Beer
Microtubule-Associated Proteins
Bioactivity
Neurodegenerative Diseases
Proteolysis
Assays
Carrier Proteins
Proteins
Light
Degradation
Substrates
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein. / Sasazawa, Yukiko; Kanagaki, Shuhei; Tashiro, Etsu; Nogawa, Toshihiko; Muroi, Makoto; Kondoh, Yasumitsu; Osada, Hiroyuki; Imoto, Masaya.

In: ACS Chemical Biology, Vol. 7, No. 5, 18.05.2012, p. 892-900.

Research output: Contribution to journalArticle

Sasazawa, Yukiko ; Kanagaki, Shuhei ; Tashiro, Etsu ; Nogawa, Toshihiko ; Muroi, Makoto ; Kondoh, Yasumitsu ; Osada, Hiroyuki ; Imoto, Masaya. / Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein. In: ACS Chemical Biology. 2012 ; Vol. 7, No. 5. pp. 892-900.
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