Beclin-1-interacting autophagy protein Atg14L targets the SNARE-associated protein Snapin to coordinate endocytic trafficking
Beclin-1-interacting autophagy protein Atg14L targets the SNARE-associated protein Snapin to coordinate endocytic trafficking
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DOI：
10.1242/jcs.100339
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发表时间：
2012-10-15
影响因子：
4
通讯作者：
Jung, Jae U.
中科院分区：
文献类型：
--
作者：
Kim, Hee Jin;Zhong, Qing;Jung, Jae U.
自噬是一种高度调控的膜重塑过程，它允许溶酶体通过将细胞质实体隔离在双膜自噬体内而使其降解。因此，自噬与内吞运输途径高度交织在一起，共享相似的分子机制。Atg14L，也被称为Beclin 1相关的自噬相关关键调节因子(Barkor)，通过其卷曲的卷曲结构域直接与Beclin 1相互作用，并增强磷脂酰肌醇3-磷酸激酶III(PI3KC3)活性，诱导自噬体膜成核，强调其在哺乳动物自噬的早期阶段中的重要作用。在这里，我们报道了Atg14L在内吞转运途径中的一个新功能，其中Atg14L与融合的SNARE效应蛋白Snapin结合并共同定位，以促进内小体成熟。Atg14L特异性地与Snapin结合，这种相互作用有效地促进了内体成熟，而不影响自噬货物的降解。因此，atg14l基因敲除显著延迟了内吞转运的晚期，内化表面受体降解的动力学被延缓。野生型Atg14L或Beclin 1结合突变体有效地补充了这种表型，但不能被其Snapin结合突变体所补充。综上所述，我们的研究表明，Atg14L作为一个多价转运效应器，调节内体成熟和自噬小体的形成，反映了高等真核生物自噬和内吞囊泡运输之间串扰的复杂性。
Autophagy is a highly regulated membrane remodeling process that allows the lysosome-mediated degradation of cytoplasmic entities by sequestrating them in double-membrane autophagosomes. Autophagy is hence highly intertwined with the endocytic trafficking pathway, sharing similar molecular machinery. Atg14L, also known as Beclin 1-associated autophagy-related key regulator (Barkor), directly interacts with Beclin 1 through its coiled-coil domain and enhances phosphatidylinositol 3-phosphate kinase class III (PI3KC3) activity to induce autophagosome membrane nucleation, highlighting its essential role in the early stage of mammalian autophagy. Here, we report a novel function of Atg14L in the endocytic trafficking pathway wherein Atg14L binds to and colocalizes with the fusogenic SNARE effector protein Snapin to facilitate endosome maturation. Atg14L specifically binds to Snapin and this interaction effectively facilitates endosomal maturation without affecting autophagic cargo degradation. Consequently, atg14l knockdown significantly delayed the late stage of endocytic trafficking, as evidenced by the retarded kinetics of internalized surface receptor degradation. This phenotype was effectively complemented by wild-type Atg14L or Beclin 1-binding mutant, but not by its Snapin-binding mutant. Taken together, our study demonstrates that Atg14L functions as a multivalent trafficking effector that regulates endosome maturation as well as autophagosome formation, reflecting the complexity of the crosstalk between autophagic and endocytic vesicle trafficking in higher eukaryotes.