Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB.
Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB.
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DOI：
10.1038/ncb3114
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发表时间：
2015-03
影响因子：
21.3
通讯作者：
Ballabio A
中科院分区：
文献类型：
--
作者：
Medina DL;Di Paola S;Peluso I;Armani A;De Stefani D;Venditti R;Montefusco S;Scotto-Rosato A;Prezioso C;Forrester A;Settembre C;Wang W;Gao Q;Xu H;Sandri M;Rizzuto R;De Matteis MA;Ballabio A
溶酶体作为细胞分解代谢途径的末端的观点受到了最近研究的挑战，这些研究显示了这个细胞器在控制细胞功能中的核心作用。在这里，我们表明，溶酶体Ca2+信号传导机制控制的磷酸酶钙调神经磷酸酶及其底物TFEB，一个主转录调节溶酶体的生物发生和自噬的活动。通过粘脂蛋白1（MCOLN 1）释放的溶酶体Ca2+激活钙调磷酸酶，钙调磷酸酶结合并使TFEB去磷酸化，从而促进其核转位。钙调神经磷酸酶的遗传和药理学抑制抑制TFEB活性在饥饿和体育锻炼，而钙调神经磷酸酶的过度表达和组成性激活有相反的效果。通过TFEB诱导自噬和溶酶体生物发生需要MCOLN 1介导的钙调磷酸酶激活，将溶酶体钙信号传导与钙调磷酸酶调节和自噬诱导联系起来。因此，溶酶体显示其自身为调节细胞内稳态的信号传导途径的枢纽。
The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca2+ signaling mechanism controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. Genetic and pharmacological inhibition of calcineurin suppressed TFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect. Induction of autophagy and lysosomal biogenesis via TFEB required MCOLN1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction. Thus, the lysosome reveals itself as a hub for the signaling pathways that regulate cellular homeostasis.