WDR41 supports lysosomal response to changes in amino acid availability.
WDR41 supports lysosomal response to changes in amino acid availability.
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DOI：
10.1091/mbc.e17-12-0703
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发表时间：
2018-09-01
影响因子：
3.3
通讯作者：
Ferguson SM
中科院分区：
文献类型：
--
作者：
Amick J;Tharkeshwar AK;Amaya C;Ferguson SM
C9orf72突变是肌萎缩侧索硬化症和额颞叶痴呆的主要原因。C9orf72蛋白经历受调节的向溶酶体的募集，并且已经广泛涉及溶酶体稳态的控制。然而，尽管有证据强烈支持C9orf72在溶酶体中的重要功能，但对溶酶体募集机制知之甚少。在这项研究中，我们确定了一个重要的作用，WDR 41，一个突出的C9orf72相互作用蛋白，在C9orf72溶酶体招聘。对人WDR 41敲除细胞的分析表明，WDR 41是将含有C9orf72和SMCR 8的蛋白复合物定位于溶酶体所必需的。这种溶酶体定位响应于氨基酸饥饿而增加，但不依赖于mTORC 1抑制或自噬诱导。此外，WDR 41本身表现出与溶酶体调节关联的平行模式。C9orf72向溶酶体的这种WDR 41依赖性募集对于溶酶体支持mTORC 1信号传导的能力至关重要，因为C9orf72向溶酶体的组成性靶向减轻了mTORC 1活化中对WDR 41的需求。总的来说，这项研究揭示了WDR 41在支持C9orf72与溶酶体的调节结合方面的重要作用，并巩固了在协调溶酶体对氨基酸可用性变化的反应中对含有更大C9orf72的蛋白质复合物的需求。
C9orf72 mutations are a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. The C9orf72 protein undergoes regulated recruitment to lysosomes and has been broadly implicated in control of lysosome homeostasis. However, although evidence strongly supports an important function for C9orf72 at lysosomes, little is known about the lysosome recruitment mechanism. In this study, we identify an essential role for WDR41, a prominent C9orf72 interacting protein, in C9orf72 lysosome recruitment. Analysis of human WDR41 knockout cells revealed that WDR41 is required for localization of the protein complex containing C9orf72 and SMCR8 to lysosomes. Such lysosome localization increases in response to amino acid starvation but is not dependent on either mTORC1 inhibition or autophagy induction. Furthermore, WDR41 itself exhibits a parallel pattern of regulated association with lysosomes. This WDR41-dependent recruitment of C9orf72 to lysosomes is critical for the ability of lysosomes to support mTORC1 signaling as constitutive targeting of C9orf72 to lysosomes relieves the requirement for WDR41 in mTORC1 activation. Collectively, this study reveals an essential role for WDR41 in supporting the regulated binding of C9orf72 to lysosomes and solidifies the requirement for a larger C9orf72 containing protein complex in coordinating lysosomal responses to changes in amino acid availability.