EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons.
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons.
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DOI：
10.1038/s41598-017-02202-4
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发表时间：
2017-05-19
影响因子：
4.6
通讯作者：
Dean C
中科院分区：
文献类型：
--
作者：
Burk K;Murdoch JD;Freytag S;Koenig M;Bharat V;Markworth R;Burkhardt S;Fischer A;Dean C
将活化的受体分选到不同的内体区室中对于活化特异性信号级联和细胞事件（包括生长和存活）是必需的。然而，参与这种分选的蛋白质还没有得到很好的理解。我们发现了EndophilinAs在将活化的BDNF-TrkB受体分选到晚期内体隔室中的新作用。缺乏所有三种EndophilinA的小鼠积累Rab 7阳性晚期内体。此外，EndophilinA差异定位于不同的内体区室，与其共同运输并使其形成微管：响应于BDNF，EndophilinA 2被募集到早期和晚期内体，EndophilinA 3被募集到Lamp 1阳性晚期内体，并且在BDNF存在和不存在的情况下与Rab 5和Rab 7共同运输，而EndophilinA 1与内体以较低水平共定位。所有三种EndophilinA的缺乏导致TrkB在EEA 1和Rab 7阳性内体中积累，并损害BDNF-TrkB依赖性存活信号级联。此外，在神经营养因子依赖性存活测定中，EndophilinA三重敲除神经元表现出增加的细胞死亡，这不能被外源性BDNF拯救。因此，EndophilinAs通过不同的内体区室差异调节活化受体分选以促进BDNF依赖性细胞存活。
The sorting of activated receptors into distinct endosomal compartments is essential to activate specific signaling cascades and cellular events including growth and survival. However, the proteins involved in this sorting are not well understood. We discovered a novel role of EndophilinAs in sorting of activated BDNF-TrkB receptors into late endosomal compartments. Mice lacking all three EndophilinAs accumulate Rab7-positive late endosomes. Moreover, EndophilinAs are differentially localized to, co-traffic with, and tubulate, distinct endosomal compartments: In response to BDNF, EndophilinA2 is recruited to both early and late endosomes, EndophilinA3 is recruited to Lamp1-positive late endosomes, and co-trafficks with Rab5 and Rab7 in both the presence and absence of BDNF, while EndophilinA1 colocalizes at lower levels with endosomes. The absence of all three EndophilinAs caused TrkB to accumulate in EEA1 and Rab7-positive endosomes, and impaired BDNF-TrkB-dependent survival signaling cascades. In addition, EndophilinA triple knockout neurons exhibited increased cell death which could not be rescued by exogenous BDNF, in a neurotrophin-dependent survival assay. Thus, EndophilinAs differentially regulate activated receptor sorting via distinct endosomal compartments to promote BDNF-dependent cell survival.