AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network.
AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network.
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DOI：
10.1091/mbc.e21-09-0473
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发表时间：
2022-10-01
影响因子：
3.3
通讯作者：
Gowrishankar, Swetha
中科院分区：
文献类型：
--
作者：
Majumder, Piyali;Edmison, Daisy;Rodger, Catherine;Patel, Sruchi;Reid, Evan;Gowrishankar, Swetha
已知适配器蛋白复合体-4或AP-4通过调节跨膜货物如ATG9A在高尔基体的分选来介导自噬小体成熟。有必要了解AP-4在神经元中的功能，因为它的四个亚基中的任何一个突变都会导致一种复杂形式的遗传性痉挛截瘫(HSP)，并伴有智能障碍。虽然AP-4参与调节ATG9A和APP等货物的运输和分配，但对其对神经元溶酶体蛋白运输、溶酶体生物发生和功能的影响知之甚少。在这项研究中，我们证明了在人类IPSC来源的神经元中，AP-4通过调节包括Sortilin 1在内的关键溶酶体受体从跨高尔基体网络到内溶酶体的输出来调节溶酶体的组成、功能和运输。此外，AP-4的丢失可能通过减少向细胞器逆行运输机械的招募而导致内切溶酶体停滞并在轴突肿胀中积聚。这些轴突溶酶体积聚的发现非常类似于在阿尔茨海默病以及模拟由痉挛蛋白突变引起的最常见形式的HSP的神经元中观察到的结果。我们的发现表明，AP-4是神经元溶酶体生物发生的关键调节因子，而溶酶体功能和轴突内溶酶体运输的改变是AP-4缺乏的HSP的潜在缺陷。此外，我们的结果还证明了人类i3Neuronal模型系统在研究AP-4缺陷小鼠和/或人类AP-4缺陷综合征中观察到的神经元表型方面的实用性。
The adaptor protein complex-4 or AP-4 is known to mediate autophagosome maturation through regulating sorting of transmembrane cargo such as ATG9A at the Golgi. There is a need to understand AP-4 function in neurons, as mutations in any of its four subunits cause a complex form of hereditary spastic paraplegia (HSP) with intellectual disability. While AP-4 has been implicated in regulating trafficking and distribution of cargo such as ATG9A and APP, little is known about its effect on neuronal lysosomal protein traffic, lysosome biogenesis, and function. In this study, we demonstrate that in human iPSC-derived neurons AP-4 regulates lysosome composition, function, and transport via regulating the export of critical lysosomal receptors, including Sortilin 1, from the trans-Golgi network to endo-lysosomes. Additionally, loss of AP-4 causes endo-lysosomes to stall and build up in axonal swellings potentially through reduced recruitment of retrograde transport machinery to the organelle. These findings of axonal lysosome buildup are highly reminiscent of those observed in Alzheimer’s disease as well as in neurons modeling the most common form of HSP, caused by spastin mutations. Our findings implicate AP-4 as a critical regulator of neuronal lysosome biogenesis and altered lysosome function and axonal endo-lysosome transport as an underlying defect in AP-4-deficient HSP. Additionally, our results also demonstrate the utility of the human i3Neuronal model system in investigating neuronal phenotypes observed in AP-4-deficient mice and/or the human AP-4 deficiency syndrome.