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Biogenesis of lysosome-related organelles complex-1 (BORC) regulates late endosomal/lysosomal size through PIKfyve-dependent phosphatidylinositol-3,5-bisphosphate.
Traffic ( IF 3.6 ) Pub Date : 2019-09-01 , DOI: 10.1111/tra.12679
Teodor E Yordanov 1 , Victoria E B Hipolito 2 , Gudrun Liebscher 1 , Georg F Vogel 1, 3 , Taras Stasyk 1 , Caroline Herrmann 1 , Stephan Geley 4 , David Teis 1 , Roberto J Botelho 2 , Michael W Hess 5 , Lukas A Huber 1, 6
Affiliation  

Mechanisms that control lysosomal function are essential for cellular homeostasis. Lysosomes adapt in size and number to cellular needs but little is known about the underlying molecular mechanism. We demonstrate that the late endosomal/lysosomal multimeric BLOC-1-related complex (BORC) regulates the size of these organelles via PIKfyve-dependent phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2 ] production. Deletion of the core BORC component Diaskedin led to increased levels of PI(3,5)P2 , suggesting activation of PIKfyve, and resulted in enhanced lysosomal reformation and subsequent reduction in lysosomal size. This process required AMP-activated protein kinase (AMPK), a known PIKfyve activator, and was additionally dependent on the late endosomal/lysosomal adaptor, mitogen-activated protein kinases and mechanistic target of rapamycin activator (LAMTOR/Ragulator) complex. Consistently, in response to glucose limitation, AMPK activated PIKfyve, which induced lysosomal reformation with increased baseline autophagy and was coupled to a decrease in lysosomal size. These adaptations of the late endosomal/lysosomal system reversed under glucose replete growth conditions. In summary, our results demonstrate that BORC regulates lysosomal reformation and size in response to glucose availability.

中文翻译:


溶酶体相关细胞器复合体-1 (BORC) 的生物发生通过 PIKfyve 依赖性磷脂酰肌醇-3,5-二磷酸调节晚期内体/溶酶体大小。



控制溶酶体功能的机制对于细胞稳态至关重要。溶酶体的大小和数量适应细胞的需要,但对其潜在的分子机制知之甚少。我们证明晚期内体/溶酶体多聚体 BLOC-1 相关复合物 (BORC) 通过 PIKfyve 依赖性磷脂酰肌醇-3,5-二磷酸 [PI(3,5)P2 ] 的产生来调节这些细胞器的大小。删除核心 BORC 成分 Diaskedin 会导致 PI(3,5)P2 水平升高,表明 PIKfyve 被激活,并导致溶酶体重组增强,随后溶酶体大小减小。该过程需要 AMP 激活蛋白激酶 (AMPK)(一种已知的 PIKfyve 激活剂),并且还依赖于晚期内体/溶酶体接头、丝裂原激活蛋白激酶和雷帕霉素激活剂 (LAMTOR/Ragulator) 复合物的机械靶标。一致地,为了响应葡萄糖限制,AMPK 激活 PIKfyve,从而诱导溶酶体重构,增加基线自噬,并导致溶酶体大小减小。晚期内体/溶酶体系统的这些适应在葡萄糖充足的生长条件下逆转。总之,我们的结果表明 BORC 响应葡萄糖可用性调节溶酶体重组和大小。
更新日期:2019-08-19
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