Late endosomes and lysosomes (endolysosomes) receive proteins and cargo from the secretory, endocytic and autophagic pathways. Although these pathways and the degradative processes of endolysosomes are well characterized, less is understood about protein traffic from these organelles. In this study, we demonstrate the direct involvement of the phosphatidylinositol 3-phosphate (PI3P)-binding SNX4 protein in membrane protein recycling from endolysosomes, and show that SNX4 is required for proper autophagic flux. We show that SNX4 mediates recycling of the lipid scramblase ATG9A, which drives expansion of nascent autophagosome membranes, from endolysosomes to early endosomes, from where ATG9A is recycled to the trans-Golgi network in a retromer-dependent manner. Upon siRNA-mediated depletion of SNX4 or the retromer component VPS35, we observed accumulation of ATG9A on endolysosomes and early endosomes, respectively. Moreover, starvation-induced autophagosome biogenesis and autophagic flux were inhibited when SNX4 was downregulated. We propose that proper ATG9A recycling by SNX4 sustains autophagy by preventing exhaustion of the available ATG9A pool.

This article has an associated First Person interview with the first author of the paper.

晚期内体和溶酶体（内溶酶体）从分泌、内吞和自噬途径接收蛋白质和货物。尽管这些途径和内溶酶体的降解过程已得到很好的表征，但对来自这些细胞器的蛋白质运输了解较少。在这项研究中，我们证明了与磷脂酰肌醇 3-磷酸 (PI3P) 结合的 SNX4 蛋白直接参与内溶酶体的膜蛋白循环，并表明 SNX4 是适当的自噬通量所必需的。我们表明 SNX4 介导脂质加扰酶 ATG9A 的再循环，它驱动新生自噬体膜从内溶酶体到早期内体的扩张，从那里 ATG9A 以逆转录酶依赖的方式循环到跨高尔基网络。在 siRNA 介导的 SNX4 或逆转录酶成分 VPS35 耗尽后，我们分别观察到ATG9A在内溶酶体和早期内体上的积累。此外，当 SNX4 被下调时，饥饿诱导的自噬体生物发生和自噬通量受到抑制。我们建议 SNX4 适当的 ATG9A 回收通过防止可用 ATG9A 池的耗尽来维持自噬。

本文与论文的第一作者进行了相关的第一人称采访。