Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes.
Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes.
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DOI：
10.15252/embr.201541382
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发表时间：
2016-06
期刊：
影响因子：
7.7
通讯作者：
Dodding MP
中科院分区：
文献类型：
--
作者：
Starling GP;Yip YY;Sanger A;Morton PE;Eden ER;Dodding MP
溶酶体的空间分布对其功能很重要，在一定程度上受细胞营养状态的控制。在这里，我们发现溶酶体相关的Birt-Hoge-Dubé(BHD)综合征肾肿瘤抑制因子毛囊蛋白(Flcn)调节这一过程。在停用血清和氨基酸后，Flcn促进溶酶体的核周聚集，并由主要与高尔基体相关的小GTP酶Rab34支持。Rab34阳性的核周膜与溶酶体接触，导致溶酶体动能降低，而Flcn基因的敲除抑制了Rab34诱导的核周溶酶体聚集。Flcn通过其C-末端Denn结构域与Rab34效应器RILP直接相互作用。使用纯化的重组蛋白，我们证明了Flcn-Denn结构域并不是Rab34的环境基金，而是将活性Rab34装载到RILP上。我们提出了一个模型，饥饿诱导的Flcn与溶酶体的结合驱动溶酶体与Rab34阳性核周膜之间形成接触部位，从而限制溶酶体的运动，从而促进它们在细胞的这一区域的保留。
The spatial distribution of lysosomes is important for their function and is, in part, controlled by cellular nutrient status. Here, we show that the lysosome associated Birt–Hoge–Dubé (BHD) syndrome renal tumour suppressor folliculin (FLCN) regulates this process. FLCN promotes the peri‐nuclear clustering of lysosomes following serum and amino acid withdrawal and is supported by the predominantly Golgi‐associated small GTPase Rab34. Rab34‐positive peri‐nuclear membranes contact lysosomes and cause a reduction in lysosome motility and knockdown of FLCN inhibits Rab34‐induced peri‐nuclear lysosome clustering. FLCN interacts directly via its C‐terminal DENN domain with the Rab34 effector RILP. Using purified recombinant proteins, we show that the FLCN‐DENN domain does not act as a GEF for Rab34, but rather, loads active Rab34 onto RILP. We propose a model whereby starvation‐induced FLCN association with lysosomes drives the formation of contact sites between lysosomes and Rab34‐positive peri‐nuclear membranes that restrict lysosome motility and thus promote their retention in this region of the cell.