Xanthohumol Impairs Autophagosome Maturation through Direct Inhibition of Valosin-Containing Protein
Xanthohumol Impairs Autophagosome Maturation through Direct Inhibition of Valosin-Containing Protein
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DOI：
10.1021/cb200492h
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发表时间：
2012-05-01
影响因子：
4
通讯作者：
Imoto, Masaya
中科院分区：
文献类型：
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作者：
Sasazawa, Yukiko;Kanagaki, Shuhei;Imoto, Masaya
自噬是一种大量的、非特异性的蛋白质降解途径，参与癌症和神经退行性疾病的发病机制。在这里，我们观察到黄腐酚（XN），一个异戊二烯化的查耳酮存在于啤酒花（啤酒花L.）和啤酒调节自噬。通过使用XN-固定化珠，含有缬氨素的蛋白（VCP）被鉴定为XN-结合蛋白。VCP已被报道是自噬体成熟的必需蛋白。使用体外下拉测定，我们表明XN直接结合到N结构域，这是已知的介导辅因子和底物结合到VCP。这些数据表明，XN抑制VCP的功能，从而允许自噬体成熟的损害，并导致微管相关蛋白1轻链3-II（LC 3-II）的积累。这是第一份证明XN作为直接结合VCP N结构域的VCP抑制剂的报告。我们的发现，XN结合并灭活VCP不仅揭示了XN调节自噬的分子机制，而且还可以解释XN如何表现出各种生物活性，以前已经报道。
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.