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The phosphatidylinositol 3-phosphate-binding protein SNX4 controls ATG9A recycling and autophagy
Journal of Cell Science ( IF 3.3 ) Pub Date : 2021-02-10 , DOI: 10.1242/jcs.250670
Anthony Ravussin 1, 2 , Andreas Brech 1, 2 , Sharon A Tooze 3 , Harald Stenmark 2, 4
Affiliation  

Anthony Ravussin, Andreas Brech, Sharon A. Tooze, and Harald Stenmark

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.



中文翻译:


磷脂酰肌醇 3-磷酸结合蛋白 SNX4 控制 ATG9A 回收和自噬



安东尼·拉武辛、安德烈亚斯·布雷希、莎朗·A·图兹和哈拉尔德·斯坦马克



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,但人们对这些细胞器的蛋白质运输知之甚少。在这项研究中,我们证明了磷脂酰肌醇 3-磷酸 (PI3P) 结合 SNX4 蛋白直接参与内溶酶体的膜蛋白回收,并表明 SNX4 是适当的自噬通量所必需的。我们发现,SNX4 介导脂质扰乱酶 ATG9A 的回收,该酶驱动新生自噬体膜的扩张,从内溶酶体到早期内体,然后 ATG9A 以逆转录酶依赖性方式再循环到反式高尔基体网络。在 siRNA 介导的 SNX4 或逆转录体成分 VPS35 耗竭后,我们观察到 ATG9A 分别在内溶酶体和早期内体上积累。此外,当 SNX4 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 适当回收 ATG9A,通过防止可用 ATG9A 池耗尽来维持自噬。


本文有对该论文第一作者的相关第一人称采访。

更新日期:2021-02-15
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