Coordination of autophagosome-lysosome fusion and transport by a Klp98A-Rab14 complex in Drosophila
Coordination of autophagosome-lysosome fusion and transport by a Klp98A-Rab14 complex in Drosophila
复制标题
DOI：
10.1242/jcs.175224
复制
发表时间：
2016-03-01
影响因子：
4
通讯作者：
Neufeld, Thomas P.
中科院分区：
文献类型：
--
作者：
Mauvezin, Caroline;Neisch, Amanda L.;Neufeld, Thomas P.
细胞物质通过自噬降解是细胞生存和稳态所必需的，并且需要细胞内自噬体通过未知机制转运到酸性溶酶体。在这里，我们发现含有px结构域的激酶Klp98A是果蝇自噬体形成、运输和成熟的新调节剂。Klp98A的缺失导致细胞中心的自噬体和溶酶体异常聚集，减少饥饿诱导的自噬小泡的形成。相反，Klp98A的过表达使自噬囊泡向细胞周围重新分布。这些影响伴随着自噬体-溶酶体融合和自噬降解的减少。相比之下，常规动力蛋白重链的缺失导致自噬体出现类似的错误定位，但不会干扰它们与溶酶体的融合，这表明囊泡融合和定位是可分离且独立的事件。Klp98A介导的融合需要内溶酶体GTPase Rab14，该酶与Klp98A相互作用并进行共定位，并且需要Klp98A进行正常定位。因此，Klp98A通过调节自噬囊泡的定位和与内溶酶体间室的相互作用来协调自噬囊泡的运动和融合。
Degradation of cellular material by autophagy is essential for cell survival and homeostasis, and requires intracellular transport of autophagosomes to encounter acidic lysosomes through unknown mechanisms. Here, we identify the PX-domain-containing kinesin Klp98A as a new regulator of autophagosome formation, transport and maturation in Drosophila. Depletion of Klp98A caused abnormal clustering of autophagosomes and lysosomes at the cell center and reduced the formation of starvation-induced autophagic vesicles. Reciprocally, overexpression of Klp98A redistributed autophagic vesicles towards the cell periphery. These effects were accompanied by reduced autophagosome-lysosome fusion and autophagic degradation. In contrast, depletion of the conventional kinesin heavy chain caused a similar mislocalization of autophagosomes without perturbing their fusion with lysosomes, indicating that vesicle fusion and localization are separable and independent events. Klp98A-mediated fusion required the endolysosomal GTPase Rab14, which interacted and colocalized with Klp98A, and required Klp98A for normal localization. Thus, Klp98A coordinates the movement and fusion of autophagic vesicles by regulating their positioning and interaction with the endolysosomal compartment.