Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling.
Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling.
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DOI：
10.1083/jcb.201411001
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发表时间：
2015-07-20
期刊：
影响因子：
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通讯作者：
Bray SJ
中科院分区：
文献类型：
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作者：
Gomez-Lamarca MJ;Snowdon LA;Seib E;Klein T;Bray SJ
逆转录酶相关的DNAJ蛋白Rme-8是正常Notch再循环所必需的，并且Rme-8的减少使细胞敏感，使得额外的分选损失逆转录酶或ESCRT-0组分具有灾难性影响。Notch信号传导是细胞命运、增殖和分化的主要调节因子。与其他信号通路一样，其活性受到细胞内运输的强烈影响。除了有助于信号激活和下调之外，运输途径之间的差异通量可导致异常Notch途径激活。研究逆转录酶相关的DNAJ蛋白Rme-8在体内的功能，我们证明了在调节Notch受体再循环中的关键作用。在不存在Rme-8的情况下，Notch在扩大的管状Rab 4阳性内体中积累，因此，信号传导受损。引人注目的是，当逆转录组分Vps 26同时耗尽时，Notch不再积累，而是异位激活。同样地，ESCRT-0组分Hrs或Stam与Rme-8组合的消耗也导致高水平的异位Notch活性。总之，这些结果突出了Rme-8在协调正常的内吞再循环途径中的重要性，并揭示了其缺乏易导致病理性Notch信号传导可能发生的状况。
The retromer-associated DNAJ protein Rme-8 is necessary for normal Notch recycling, and reductions in Rme-8 sensitize cells so that additional loss-of-sorting retromer or ESCRT-0 components have catastrophic effects. Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.