Alternative autophagy is an Atg5/Atg7-independent type of autophagy that contributes to various physiological events. We here identify Wipi3 as a molecule essential for alternative autophagy, but which plays minor roles in canonical autophagy. Wipi3 binds to Golgi membranes and is required for the generation of isolation membranes. We establish neuron-specific Wipi3-deficient mice, which show behavioral defects, mainly as a result of cerebellar neuronal loss. The accumulation of iron and ceruloplasmin is also found in the neuronal cells. These abnormalities are suppressed by the expression of Dram1, which is another crucial molecule for alternative autophagy. Although Atg7-deficient mice show similar phenotypes to Wipi3-deficient mice, electron microscopic analysis shows that they have completely different subcellular morphologies, including the morphology of organelles. Furthermore, most Atg7/Wipi3 double-deficient mice are embryonic lethal, indicating that Wipi3 functions to maintain neuronal cells via mechanisms different from those of canonical autophagy.

替代性自噬是一种独立于Atg5 / Atg7的自噬，可导致各种生理事件。我们在这里将Wipi3识别为替代自噬必不可少的分子，但在规范自噬中起着较小的作用。Wipi3结合高尔基体膜，是生成隔离膜所必需的。我们建立神经元特定的Wipi3缺陷小鼠，表现出行为缺陷，主要是由于小脑神经元丢失。在神经元细胞中也发现了铁和铜蓝蛋白的积累。这些异常被Dram1的表达抑制，Dram1是另一种自噬的关键分子。虽然ATG7 -缺陷小鼠表现出与Wipi3缺陷小鼠相似的表型，电子显微镜分析显示它们具有完全不同的亚细胞形态，包括细胞器形态。此外，大多数Atg7 / Wipi3双缺陷小鼠都具有胚胎致死性，表明Wipi3的功能是通过不同于典型自噬的机制来维持神经元细胞。