Wang Shixuan, Livingston Man J, Su Yunchao, Dong Zheng
a Department of Cellular Biology and Anatomy ; Medical College of Georgia; Georgia Reagents University and Charlie Norwood VA Medical Center ; Augusta , GA USA.
Autophagy. 2015 Apr 3;11(4):607-16. doi: 10.1080/15548627.2015.1023983.
Primary cilium is an organelle that plays significant roles in a number of cellular functions ranging from cell mechanosensation, proliferation, and differentiation to apoptosis. Autophagy is an evolutionarily conserved cellular function in biology and indispensable for cellular homeostasis. Both cilia and autophagy have been linked to different types of genetic and acquired human diseases. Their interaction has been suggested very recently, but the underlying mechanisms are still not fully understood. We examined autophagy in cells with suppressed cilia and measured cilium length in autophagy-activated or -suppressed cells. It was found that autophagy was repressed in cells with short cilia. Further investigation showed that MTOR activation was enhanced in cilia-suppressed cells and the MTOR inhibitor rapamycin could largely reverse autophagy suppression. In human kidney proximal tubular cells (HK2), autophagy induction was associated with cilium elongation. Conversely, autophagy inhibition by 3-methyladenine (3-MA) and chloroquine (CQ) as well as bafilomycin A1 (Baf) led to short cilia. Cilia were also shorter in cultured atg5-knockout (KO) cells and in atg7-KO kidney proximal tubular cells in mice. MG132, an inhibitor of the proteasome, could significantly restore cilium length in atg5-KO cells, being concomitant with the proteasome activity. Together, the results suggest that cilia and autophagy regulate reciprocally through the MTOR signaling pathway and ubiquitin-proteasome system.
初级纤毛是一种细胞器，在从细胞机械感受、增殖、分化到细胞凋亡等多种细胞功能中发挥着重要作用。自噬是生物学中一种进化保守的细胞功能，对细胞内稳态不可或缺。纤毛和自噬都与不同类型的遗传性和后天性人类疾病有关。它们之间的相互作用最近才被提出，但潜在机制仍未完全了解。我们检测了纤毛受抑制的细胞中的自噬，并测量了自噬激活或受抑制的细胞中的纤毛长度。结果发现，纤毛短的细胞中自噬受到抑制。进一步研究表明，纤毛受抑制的细胞中MTOR激活增强，MTOR抑制剂雷帕霉素可在很大程度上逆转自噬抑制。在人肾近端小管细胞（HK2）中，自噬诱导与纤毛伸长有关。相反，3-甲基腺嘌呤（3-MA）、氯喹（CQ）以及巴弗洛霉素A1（Baf）抑制自噬会导致纤毛变短。在培养的自噬相关基因5敲除（KO）细胞和小鼠自噬相关基因7敲除的肾近端小管细胞中，纤毛也较短。蛋白酶体抑制剂MG132可显著恢复自噬相关基因5敲除细胞中的纤毛长度，这与蛋白酶体活性相伴。总之，这些结果表明，纤毛和自噬通过MTOR信号通路和泛素-蛋白酶体系统相互调节。
