Autophagic elimination of ribosomes during spermiogenesis provides energy for flagellar motility
Autophagic elimination of ribosomes during spermiogenesis provides energy for flagellar motility
复制标题
DOI：
10.1016/j.devcel.2021.07.015
复制
发表时间：
2021-08-23
影响因子：
11.8
通讯作者：
Lu, Kefeng
中科院分区：
文献类型：
--
作者：
Lei, Yuqing;Zhang, Xueguang;Lu, Kefeng
自噬起始是如何调控的，这种调控的功能意义是什么，目前还不清楚。在这里，我们通过将PIK3C3-C1招募到吞噬体组装位点（PAS）来表征酵母Vac8在自噬启动中的作用。这种招募依赖于Vac8的棕榈酰化及其结合PIK3C3-C1的中间ARM结构域。vac8介导的PIK3C3-C1锚定促进了PtdIns3P在PAS的生成和PtdIns3P结合蛋白Atg18-Atg2的募集。Vac8的小鼠同源物ARMC3是保守的，在小鼠睾丸的自噬中起作用。缺乏ARMC3的小鼠具有正常的生存能力，但表现出完全的雄性不育。蛋白质组学分析表明，缺乏armc3的精子细胞质核糖体的自噬降解被阻断，导致线粒体能量水平低下和鞭毛不动。这些研究揭示了Vac8/ARMC3在ptdins3激酶锚定PAS中的功能及其在哺乳动物精子发生中的物理意义，具有生殖组织特异性自噬功能。
How autophagy initiation is regulated and what the functional significance of this regulation is are unknown. Here, we characterized the role of yeast Vac8 in autophagy initiation through recruitment of PIK3C3-C1 to the phagophore assembly site (PAS). This recruitment is dependent on the palmitoylation of Vac8 and on its middle ARM domains for binding PIK3C3-C1. Vac8-mediated anchoring of PIK3C3-C1 promotes PtdIns3P generation at the PAS and recruitment of the PtdIns3P binding protein Atg18-Atg2. The mouse homolog of Vac8, ARMC3, is conserved and functions in autophagy in mouse testes. Mice lacking ARMC3 have normal viability but show complete male infertility. Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella. These studies uncovered a function of Vac8/ARMC3 in PtdIns3-kinase anchoring at the PAS and its physical significance in mammalian spermatogenesis with a germ tissue-specific autophagic function.