Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation.
Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation.
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DOI：
10.1038/s41467-023-39643-7
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发表时间：
2023-07-03
影响因子：
16.6
通讯作者：
Ballabio, Andrea
中科院分区：
文献类型：
--
作者：
Calcagni, Alessia;Staiano, Leopoldo;Zampelli, Nicolina;Minopoli, Nadia;Herz, Niculin J.;Di Tullio, Giuseppe;Huynh, Tuong;Monfregola, Jlenia;Esposito, Alessandra;Cirillo, Carmine;Bajic, Aleksandar;Zahabiyon, Mahla;Curnock, Rachel;Polishchuk, Elena;Parkitny, Luke;Medina, Diego Luis;Pastore, Nunzia;Cullen, Peter J.;Parenti, Giancarlo;De Matteis, Maria Antonietta;Grumati, Paolo;Ballabio, Andrea
Batten病是最具破坏性的神经退行性溶酶体贮积症之一，由CLN 3突变引起。在这里，我们表明，CLN 3是一个囊泡贩运枢纽连接高尔基体和溶酶体车厢。蛋白质组学分析表明，CLN 3与几种溶酶体内运输蛋白相互作用，包括非阳离子依赖性甘露糖6磷酸受体（CI-M6 PR），它协调溶酶体酶靶向溶酶体。CLN 3消耗导致CI-M6 PR的错误运输、溶酶体酶的错误分选和缺陷性自噬溶酶体重组。相反，CLN 3过表达促进多个溶酶体小管的形成，其是自噬和CI-M6 PR依赖性的，产生新形成的原溶酶体。总之，我们的研究结果表明，CLN 3作为溶酶体酶的M6 P依赖性运输和溶酶体重组途径之间的联系发挥作用，解释了Batten病中溶酶体功能的整体损害。CLN 3突变导致Batten病，一种毁灭性的神经退行性溶酶体储存病。在这里，作者发现CLN 3在溶酶体蛋白的运输和自噬溶酶体重组中起着至关重要的作用。
Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease. CLN3 mutations cause Batten disease, a devastating neurodegenerative lysosomal storage disease. Here, the authors discovered that CLN3 plays a crucial role in both trafficking of lysosomal proteins and autophagic lysosomal reformation.
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影响因子：
14.9
作者：
Jensen LJ;Kuhn M;Stark M;Chaffron S;Creevey C;Muller J;Doerks T;Julien P;Roth A;Simonovic M;Bork P;von Mering C
通讯作者：
von Mering C
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影响因子：
3.3
作者：
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影响因子：
3.3
作者：
Hebbar S;Khandelwal A;Jayashree R;Hindle SJ;Chiang YN;Yew JY;Sweeney ST;Schwudke D
通讯作者：
Schwudke D
影响因子：
3.2
作者：
Chattopadhyay, S;Muzaffar, NE;Pearce, DA
通讯作者：
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影响因子：
12.4
作者：
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通讯作者：
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