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Nat Cell Biol. 2012 Sep;14(9):924-34. doi: 10.1038/ncb2557. Epub 2012 Aug 12.

Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation.

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State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University-Peking University Center for Life Sciences, School of Life Science, Tsinghua University, Beijing 100084, China.


Autophagy is a lysosome-based degradation pathway. During autophagy, lysosomes fuse with autophagosomes to form autolysosomes. Following starvation-induced autophagy, nascent lysosomes are formed from autolysosomal membranes through an evolutionarily conserved cellular process, autophagic lysosome reformation (ALR), which is critical for maintaining lysosome homeostasis. Here we report that clathrin and phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulate ALR. Combining a screen of candidates identified through proteomic analysis of purified ALR tubules, and large-scale RNAi knockdown, we unveiled a tightly regulated molecular pathway that controls lysosome homeostasis, in which clathrin and PtdIns(4,5)P(2) are the central components. Our functional study demonstrates the central role of clathrin and its associated proteins in cargo sorting, phospholipid conversion, initiation of autolysosome tubulation, and proto-lysosome budding during ALR. Our data not only uncover a molecular pathway by which lysosome homeostasis is maintained through the ALR process, but also reveal unexpected functions of clathrin and PtdIns(4,5)P(2) in lysosome homeostasis.

[Indexed for MEDLINE]

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