PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation
PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation
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DOI：
10.1083/jcb.201906076
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发表时间：
2020-01-06
影响因子：
7.8
通讯作者：
Ferguson, Shawn M.
中科院分区：
文献类型：
--
作者：
Amick, Joseph;Tharkeshwar, Arun Kumar;Ferguson, Shawn M.
C9orf72蛋白是正常溶酶体功能所必需的。为了支持这些功能，C9orf72与SMCR 8和WDR 41形成异源三聚体复合物，当氨基酸缺乏时，该复合物被募集到溶酶体。这些性质提出了关于C9orf72复合物的溶酶体结合伴侣的身份和调节溶酶体上C9orf72复合物丰度的氨基酸传感机制的问题。我们现在证明，与溶酶体阳离子氨基酸转运蛋白PQLC 2的相互作用介导C9orf72复杂的招聘溶酶体。这是通过PQLC 2和WDR 41之间的相互作用实现的。PQLC 2和C9orf72复合物之间的相互作用受到精氨酸、赖氨酸和组氨酸的负调节，这些氨基酸是PQLC 2穿过溶酶体膜转运的。这些结果定义了一个新的作用PQLC 2在调节招聘的C9orf72复合体的溶酶体，并揭示了一种新的机制，使细胞的感觉和响应的变化，在溶酶体内的阳离子氨基酸的可用性。
The C9orf72 protein is required for normal lysosome function. In support of such functions, C9orf72 forms a heterotrimeric complex with SMCR8 and WDR41 that is recruited to lysosomes when amino acids are scarce. These properties raise questions about the identity of the lysosomal binding partner of the C9orf72 complex and the amino acid-sensing mechanism that regulates C9orf72 complex abundance on lysosomes. We now demonstrate that an interaction with the lysosomal cationic amino acid transporter PQLC2 mediates C9orf72 complex recruitment to lysosomes. This is achieved through an interaction between PQLC2 and WDR41. The interaction between PQLC2 and the C9orf72 complex is negatively regulated by arginine, lysine, and histidine, the amino acids that PQLC2 transports across the membrane of lysosomes. These results define a new role for PQLC2 in the regulated recruitment of the C9orf72 complex to lysosomes and reveal a novel mechanism that allows cells to sense and respond to changes in the availability of cationic amino acids within lysosomes.