LAMTOR1 inhibition of TRPML1-dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function.
LAMTOR1 inhibition of TRPML1-dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function.
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DOI：
10.15252/embj.2021108119
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发表时间：
2022-03-01
期刊：
影响因子：
--
通讯作者：
Bi X
中科院分区：
文献类型：
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作者：
Sun J;Liu Y;Hao X;Lin W;Su W;Chiang E;Baudry M;Bi X
溶酶体不仅作为降解区室，而且作为动态的细胞内钙离子库。瞬时受体电位粘磷脂1（TRPML 1）通道介导溶酶体Ca 2+释放，从而参与多种细胞功能。五聚体Ragulator复合物在mTORC 1的活化中起关键作用，也参与溶酶体运输并通过其LAMTOR 1亚基锚定到溶酶体。在这里，我们报告了Ragulator通过LAMTOR 1介导的TRPML 1活性的紧张性抑制作用限制海马神经元树突中的溶酶体运输，独立于mTORC 1。LAMTOR 1通过其N末端结构域与TRPML 1直接相互作用。通过LAMTOR 1缺失或通过破坏LAMTOR 1-TRPML 1结合来消除海马神经元中的这种抑制，增加TRPML 1介导的Ca 2+释放，并促进由动力蛋白驱动的树突状溶酶体运输。成年小鼠海马CA 1区LAMTOR 1缺失导致突触可塑性改变，以及TRPML 1激活导致物体识别记忆和情境恐惧条件反射受损。从机制上讲，突触可塑性的变化与钙调神经磷酸酶和溶酶体降解引起的GluA 1去磷酸化增加有关。因此，LAMTOR 1介导的TRPML 1抑制对于调节树突状溶酶体运动、突触可塑性和学习至关重要。溶酶体Ragulator复合物通过以mTORC 1非依赖性方式抑制TRPML 1介导的Ca 2+释放来调节突触可塑性和学习。
Lysosomes function not only as degradatory compartments but also as dynamic intracellular calcium ion stores. The transient receptor potential mucolipin 1 (TRPML1) channel mediates lysosomal Ca2+ release, thereby participating in multiple cellular functions. The pentameric Ragulator complex, which plays a critical role in the activation of mTORC1, is also involved in lysosomal trafficking and is anchored to lysosomes through its LAMTOR1 subunit. Here, we report that the Ragulator restricts lysosomal trafficking in dendrites of hippocampal neurons via LAMTOR1‐mediated tonic inhibition of TRPML1 activity, independently of mTORC1. LAMTOR1 directly interacts with TRPML1 through its N‐terminal domain. Eliminating this inhibition in hippocampal neurons by LAMTOR1 deletion or by disrupting LAMTOR1‐TRPML1 binding increases TRPML1‐mediated Ca2+ release and facilitates dendritic lysosomal trafficking powered by dynein. LAMTOR1 deletion in the hippocampal CA1 region of adult mice results in alterations in synaptic plasticity, and in impaired object‐recognition memory and contextual fear conditioning, due to TRPML1 activation. Mechanistically, changes in synaptic plasticity are associated with increased GluA1 dephosphorylation by calcineurin and lysosomal degradation. Thus, LAMTOR1‐mediated inhibition of TRPML1 is critical for regulating dendritic lysosomal motility, synaptic plasticity, and learning. The lysosomal Ragulator complex modulates synaptic plasticity and learning by inhibiting TRPML1‐mediated Ca2+ release in an mTORC1‐independent manner.