Recycling endosomal CD133 functions as an inhibitor of autophagy at the pericentrosomal region
Recycling endosomal CD133 functions as an inhibitor of autophagy at the pericentrosomal region
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DOI：
10.1038/s41598-019-39229-8
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发表时间：
2019-02-19
影响因子：
4.6
通讯作者：
Nakagawara, Akira
中科院分区：
文献类型：
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作者：
Izumi, Hideki;Li, Yuanyuan;Nakagawara, Akira
CD133是一种跨膜蛋白，主要定位于造血干细胞和神经干细胞以及癌症干细胞的质膜。虽然CD133也定位于细胞质，但细胞质CD133的作用机制和功能目前仍不清楚。我们在此证明，当Src家族激酶活性较弱时，CD133与HDAC 6相互作用，并通过基于动力蛋白的交通系统在内化和内体形成后被转运到核周围区域。然后，通过再循环内体，将外核粒体CD 133再循环至质膜。在核粒体周围区域，内体CD133捕获GABARAP，自噬的起始物，并抑制GABARAP介导的ULK1活化和随后的自噬起始。此外，粒体周围CD 133通过抑制自噬抑制细胞分化，例如初级纤毛形成和神经突生长。因此，本研究结果提供的证据表明，pericentrosomal CD 133具有通过抑制自噬来维持细胞未分化状态的独特性质。
CD133 is a transmembranous protein that mainly localises to the plasma membrane in haematopoietic and neural stem cells as well as cancer stem cells. Although CD133 also localises to the cytoplasm, the mechanism of action and function of cytoplasmic CD133 currently remain unknown. We herein demonstrated that when Src family kinase activity is weak, CD133 interacts with HDAC6 and is transported to the pericentrosomal region after internalization and endosome formation via the dynein-based traffic system. Pericentrosomal CD133 is then recycled to the plasma membrane via recycling endosomes. At the pericentrosomal region, endosomal CD133 captures GABARAP, an initiator of autophagy, and inhibits GABARAP-mediated ULK1 activation and the subsequent initiation of autophagy. Furthermore, pericentrosomal CD133 suppresses cell differentiation, such as primary cilium formation and neurite outgrowth, by inhibiting autophagy. Thus, the present results provide evidence to suggest that pericentrosomal CD133 has the unique property of maintaining the undifferentiated status of cells by inhibiting autophagy.