The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase.
The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase.
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DOI：
10.1042/bj20150219
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Brenman JE
中科院分区：
文献类型：
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作者：
Onyenwoke RU;Sexton JZ;Yan F;Díaz MC;Forsberg LJ;Major MB;Brenman JE
溶酶体贮积症 (LSD) IV 型粘脂沉积症 (MLIV) 的确切机制尚不清楚。在本研究中，我们提供了 mTOR 通过磷酸化调节负责 MLIV 的溶酶体通道的打开和关闭的证据。自噬是一条复杂的途径，受众多信号事件的调节，这些信号事件可回收大分子，并且可能在溶酶体贮积症 (LSD) 中受到干扰。在自噬过程中，溶酶体 Ca2+ 流出通道 TRPML1 [瞬时受体电位粘脂蛋白 1 (MCOLN1)]（也称为 MCOLN1）的异常调节是导致人类 LSD 粘脂沉积症 IV 型 (MLIV) 的唯一原因；然而，这种 LSD 病理学发展的确切机制尚不清楚。在本研究中，我们提供的证据表明，雷帕霉素 (TOR) 是一种营养敏感蛋白激酶，可负向调节自噬，其靶点直接靶向并灭活 TRPML1 通道，从而通过磷酸化实现功能性自噬。此外，将这些磷酸化位点突变为不可磷酸化残基被证明可以阻断 TRPML1 通道的 TOR 调节。这些发现提出了 TOR 活性如何调节 TRPML1 通道的机制。
The exact mechanisms underlying the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV) are unclear. In the present study, we provide evidence that mTOR regulates the opening and closing of the lysosomal channel responsible for MLIV through phosphorylation. Autophagy is a complex pathway regulated by numerous signalling events that recycles macromolecules and may be perturbed in lysosomal storage disorders (LSDs). During autophagy, aberrant regulation of the lysosomal Ca2+ efflux channel TRPML1 [transient receptor potential mucolipin 1 (MCOLN1)], also known as MCOLN1, is solely responsible for the human LSD mucolipidosis type IV (MLIV); however, the exact mechanisms involved in the development of the pathology of this LSD are unknown. In the present study, we provide evidence that the target of rapamycin (TOR), a nutrient-sensitive protein kinase that negatively regulates autophagy, directly targets and inactivates the TRPML1 channel and thereby functional autophagy, through phosphorylation. Further, mutating these phosphorylation sites to unphosphorylatable residues proved to block TOR regulation of the TRPML1 channel. These findings suggest a mechanism for how TOR activity may regulate the TRPML1 channel.