Beclin 1 Forms Two Distinct Phosphatidylinositol 3-Kinase Complexes with Mammalian Atg14 and UVRAG
Beclin 1 Forms Two Distinct Phosphatidylinositol 3-Kinase Complexes with Mammalian Atg14 and UVRAG
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DOI：
10.1091/mbc.e08-01-0080
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发表时间：
2008-12-01
影响因子：
3.3
通讯作者：
Mizushima, Noboru
中科院分区：
文献类型：
--
作者：
Itakura, Eisuke;Kishi, Chieko;Mizushima, Noboru
III类磷脂酰肌醇3-激酶（PI 3-激酶）调节多个膜运输。在酵母中，已知两种不同的PI 3-激酶复合物：复合物I（Vps 34、Vps 15、Vps 30/Atg 6和Atg 14）参与自噬，复合物II（Vps 34、Vps 15、Vps 30/Atg 6和Vps 38）在液泡蛋白分选途径中起作用。Atg 14和Vps 38在诱导两种复合物发挥不同功能方面很重要。在哺乳动物中，Vps 34、Vps 15和Vps 30/Atg 6的对应物已分别被鉴定为Vps 34、p150和Beclin 1。然而，Atg 14和Vps 38的直向同源物仍然未知。我们确定了Atg 14和Vps 38的推定哺乳动物同源物。Vps 38候选基因与已报道的Beclin 1相互作用蛋白UV辐射抗性相关基因（UVRAG）相同。虽然人Atg 14和UVRAG都与Beclin 1和Vps 34相互作用，但Atg 14和UVRAG不存在于同一复合物中。虽然Atg 14存在于自噬分离膜上，但UVRAG主要与Rab 9阳性内体相关。在HeLa细胞中沉默人Atg 14抑制自噬体形成。Atg 14的卷曲螺旋区域与Vps 34和Beclin 1结合所需的是自噬所必需的。这些结果表明，哺乳动物细胞有至少两个不同的III类PI 3-激酶复合物，这可能在不同的膜运输途径的功能。
Class III phosphatidylinositol 3-kinase (PI3-kinase) regulates multiple membrane trafficking. In yeast, two distinct PI3-kinase complexes are known: complex I (Vps34, Vps15, Vps30/Atg6, and Atg14) is involved in autophagy, and complex II (Vps34, Vps15, Vps30/Atg6, and Vps38) functions in the vacuolar protein sorting pathway. Atg14 and Vps38 are important in inducing both complexes to exert distinct functions. In mammals, the counterparts of Vps34, Vps15, and Vps30/Atg6 have been identified as Vps34, p150, and Beclin 1, respectively. However, orthologues of Atg14 and Vps38 remain unknown. We identified putative mammalian homologues of Atg14 and Vps38. The Vps38 candidate is identical to UV irradiation resistance-associated gene (UVRAG), which has been reported as a Beclin 1-interacting protein. Although both human Atg14 and UVRAG interact with Beclin 1 and Vps34, Atg14, and UVRAG are not present in the same complex. Although Atg14 is present on autophagic isolation membranes, UVRAG primarily associates with Rab9-positive endosomes. Silencing of human Atg14 in HeLa cells suppresses autophagosome formation. The coiled-coil region of Atg14 required for binding with Vps34 and Beclin 1 is essential for autophagy. These results suggest that mammalian cells have at least two distinct class III PI3-kinase complexes, which may function in different membrane trafficking pathways.