Rab35 GTPase recruits NPD52 to autophagy targets
Rab35 GTPase recruits NPD52 to autophagy targets
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DOI：
10.15252/embj.201796463
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发表时间：
2017-09-15
期刊：
影响因子：
11.4
通讯作者：
Nakagawa, Ichiro
中科院分区：
文献类型：
--
作者：
Minowa-Nozawa, Atsuko;Nozawa, Takashi;Nakagawa, Ichiro
自噬靶向细胞内分子、受损的细胞器和入侵的病原体以在溶酶体中降解。最近的研究已经确定了自噬受体，通过结合泛素化靶点（包括NDP 52）来促进这一过程。在这里，我们证明了小的鸟苷三磷酸酶Rab 35指导NDP 52到多种形式的自噬的相应目标。Rab 35的活性GTP结合形式在含有细菌的内体上积累，Rab 35直接结合并募集NDP 52至内化的细菌。此外，Rab 35促进NDP 52与泛素的相互作用。这个过程被TBC 1D 10A抑制，TBC 1D 10A是一种使Rab 35失活的GAP，但通过与NDP 52相关的TBK 1激酶的自噬激活来刺激。Rab 35、TBC 1D 10A和TBK 1分别调节NDP 52向受损线粒体和自噬体的募集，以促进自噬体的线粒体自噬和成熟。我们认为Rab 35-GTP通过募集自噬受体NDP 52而成为自噬的重要调节因子。
Autophagy targets intracellular molecules, damaged organelles, and invading pathogens for degradation in lysosomes. Recent studies have identified autophagy receptors that facilitate this process by binding to ubiquitinated targets, including NDP52. Here, we demonstrate that the small guanosine triphosphatase Rab35 directs NDP52 to the corresponding targets of multiple forms of autophagy. The active GTP-bound form of Rab35 accumulates on bacteria-containing endosomes, and Rab35 directly binds and recruits NDP52 to internalized bacteria. Additionally, Rab35 promotes interaction of NDP52 with ubiquitin. This process is inhibited by TBC1D10A, a GAP that inactivates Rab35, but stimulated by autophagic activation via TBK1 kinase, which associates with NDP52. Rab35, TBC1D10A, and TBK1 regulate NDP52 recruitment to damaged mitochondria and to autophagosomes to promote mitophagy and maturation of autophagosomes, respectively. We propose that Rab35-GTP is a critical regulator of autophagy through recruiting autophagy receptor NDP52.