PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex.
PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex.
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DOI：
10.1038/ncb2848
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发表时间：
2013-10
影响因子：
21.3
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中科院分区：
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内质网-高尔基体膜运输和自噬是交叉的运输途径，受到严格调控，对于体内平衡、发育和疾病至关重要。在这里，我们将 UVRAG（一种 Beclin1 结合自噬因子）鉴定为 PI(3)P 结合蛋白，其内质网定位依赖于 PI(3)P。我们进一步表明，UVRAG 与 RINT-1 相互作用，并作为包含 RINT-1 的 ER 束缚复合物的组成部分，该复合物将磷酸肌醇代谢与 COPI 囊泡束缚结合起来。 UVRAG 的移位或敲除严重破坏了 COPI 货物向 ER 和高尔基体的完整性转移。有趣的是，自噬导致 UVRAG 从 ER 系链上解离，而 UVRAG 又与 Bif-1-Beclin-PI(3)KC3 复合物协同作用，动员 Atg9 易位以形成自噬体。这些发现确定了一种调节机制，通过UVRAG、磷酸肌醇及其调节因子之间的物理和功能相互作用来协调高尔基体-ER逆行和自噬相关的囊泡运输事件，从而确保膜运输的时空保真度和细胞器稳态的维持。
ER-Golgi membrane transport and autophagy are intersecting trafficking pathways that are tightly regulated and crucial for homeostasis, development and diseases. Here, we identify UVRAG, a Beclin1-binding autophagic factor, as a PI(3)P-binding protein that depends on PI(3)P for its ER localization. We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity. Intriguingly, autophagy caused the dissociation of UVRAG from the ER tether, which in turn worked in concert with the Bif-1-Beclin-PI(3)KC3 complex to mobilize Atg9 translocation for autophagosome formation. These findings identify a regulatory mechanism that coordinates Golgi-ER retrograde and autophagy-related vesicular trafficking events through physical and functional interactions between UVRAG, phosphoinositide, and their regulatory factors, thereby ensuring spatiotemporal fidelity of membrane trafficking and maintenance of organelle homeostasis.