Vps21 Directs the PI3K-PI(3)P-Atg21-Atg16 Module to Phagophores via Vps8 for Autophagy.
Vps21 Directs the PI3K-PI(3)P-Atg21-Atg16 Module to Phagophores via Vps8 for Autophagy.
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Vps21 通过 Vps8 将 PI3K-PI(3)P-Atg21-Atg16 模块引导至吞噬细胞进行自噬
DOI：
10.3390/ijms23179550
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发表时间：
2022-08-23
影响因子：
5.6
通讯作者：
Liang, Yongheng
中科院分区：
文献类型：
--
作者：
Zhao, Lei;You, Weiming;Sun, Dan;Xu, Hui;You, Xia;Xu, Haiqian;Wu, Zulin;Xie, Zhiping;Liang, Yongheng
关键词：
磷脂酰肌醇3-磷酸（PI(3)P）在内吞、吞噬和自噬中起重要作用。PI(3)P是由III类磷脂酰肌醇3-激酶（PI3K）复合物的Vps34产生的。vp334 - pi3k复合体可分为II类（含Vps38，内体）和I类（含Atg14，自噬体）。大多数PI(3)Ps与内体膜有关。在酵母中，Vps34和PI(3)P的内体定位受到vps21模块蛋白的严格调控。在酵母噬菌体组装位点（PAS）或哺乳动物的omega -小体上，PI(3)P结合与磷酸肌苷（WIPI）蛋白相互作用的WD-repeat蛋白，进一步募集Atg5-Atg12·Atg16和Atg8-PE （LC3-II）两个偶联系统，启动自噬。然而，自噬过程中PI(3)P的时空调控尚不清楚。因此，在本研究中，我们确定了Vps21对Vps8、Vps34、Atg21、Atg8和Atg16在诱导自噬过程中的定位和相互作用的影响。结果表明，Vps8-Vps34和Vps34-Atg21在核内体上和Atg21-Atg8/Atg16在PAS上的连续共定位和相互作用需要Vps21。除了PI3K复合物II亚基Vps34和Vps38在核内体上的定位被破坏外，vps21∆细胞中PI3K复合物I亚基Vps34和Atg14以及Atg21的定位也被部分破坏。vps21∆细胞中PI3K-PI(3)P-Atg21-Atg16轴受损可能会延迟自噬，这与Atg21缺失时早期自噬延迟一致。本研究首次揭示了Vps21在自噬过程中对PI3K-PI(3)P-Atg21-Atg16模块的上游顺序调控。
Phosphatidylinositol 3-phosphate (PI(3)P) serves important functions in endocytosis, phagocytosis, and autophagy. PI(3)P is generated by Vps34 of the class III phosphatidylinositol 3-kinase (PI3K) complex. The Vps34-PI3K complex can be divided into Vps34-PI3K class II (containing Vps38, endosomal) and Vps34-PI3K class I (containing Atg14, autophagosomal). Most PI(3)Ps are associated with endosomal membranes. In yeast, the endosomal localization of Vps34 and PI(3)P is tightly regulated by Vps21-module proteins. At yeast phagophore assembly site (PAS) or mammalian omegasomes, PI(3)P binds to WD-repeat protein interacting with phosphoinositide (WIPI) proteins to further recruit two conjugation systems, Atg5-Atg12·Atg16 and Atg8-PE (LC3-II), to initiate autophagy. However, the spatiotemporal regulation of PI(3)P during autophagy remains obscure. Therefore, in this study, we determined the effect of Vps21 on localization and interactions of Vps8, Vps34, Atg21, Atg8, and Atg16 upon autophagy induction. The results showed that Vps21 was required for successive colocalizations and interactions of Vps8-Vps34 and Vps34-Atg21 on endosomes, and Atg21-Atg8/Atg16 on the PAS. In addition to disrupted localization of the PI3K complex II subunits Vps34 and Vps38 on endosomes, the localization of the PI3K complex I subunits Vps34 and Atg14, as well as Atg21, was partly disrupted from the PAS in vps21∆ cells. The impaired PI3K-PI(3)P-Atg21-Atg16 axis in vps21∆ cells might delay autophagy, which is consistent with the delay of early autophagy when Atg21 was absent. This study provides the first insight into the upstream sequential regulation of the PI3K-PI(3)P-Atg21-Atg16 module by Vps21 in autophagy.
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发表时间：
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期刊：
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影响因子：
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作者：
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