Park Jong Kook, Peng Han, Katsnelson Julia, Yang Wending, Kaplan Nihal, Dong Ying, Rappoport Joshua Z, He CongCong, Lavker Robert M
Department of Dermatology, Northwestern University, Chicago, IL 60611.
Rush Medical Center, Chicago, IL 60615.
J Cell Biol. 2016 Dec 5;215(5):667-685. doi: 10.1083/jcb.201604032. Epub 2016 Nov 21.
Macropinocytosis, by which cells ingest large amounts of fluid, and autophagy, the lysosome-based catabolic process, involve vesicular biogenesis (early stage) and turnover (end stage). Much is known about early-stage events; however, our understanding of how the end stages of these processes are governed is incomplete. Here we demonstrate that the microRNA-103/107(miR-103/107) family, which is preferentially expressed in the stem cell-enriched limbal epithelium, coordinately regulates aspects of both these activities. Loss of miR-103/107 causes dysregulation of macropinocytosis with the formation of large vacuoles, primarily through up-regulation of Src, Ras, and Ankfy1. Vacuole accumulation is not a malfunction of early-stage autophagy; rather, miR-103/107 ensure proper end-stage autophagy by regulating diacylglycerol/protein kinase C and cyclin-dependent kinase 5 signaling, which enables dynamin to function in vacuole clearance. Our findings unveil a key biological function for miR-103/107 in coordinately suppressing macropinocytosis and preserving end-stage autophagy, thereby contributing to maintenance of a stem cell-enriched epithelium.
巨胞饮作用是细胞摄取大量液体的过程，而自噬是以溶酶体为基础的分解代谢过程，二者都涉及囊泡生物发生（早期阶段）和周转（终末阶段）。目前对早期事件已有很多了解；然而，我们对这些过程的终末阶段是如何调控的认识还不完整。在这里，我们证明了在富含干细胞的角膜缘上皮中优先表达的微小RNA-103/107（miR-103/107）家族，协同调节这两种活动的各个方面。miR-103/107的缺失会导致巨胞饮作用失调并形成大液泡，主要是通过Src、Ras和Ankfy1的上调。液泡积累并非早期自噬的功能失调；相反，miR-103/107通过调节二酰基甘油/蛋白激酶C和细胞周期蛋白依赖性激酶5信号通路来确保适当的终末阶段自噬，这使得发动蛋白能够在液泡清除中发挥作用。我们的研究结果揭示了miR-103/107在协同抑制巨胞饮作用和维持终末阶段自噬方面的关键生物学功能，从而有助于维持富含干细胞的上皮。
