Local membrane source gathering by p62 body drives autophagosome formation

Xuezhao Feng, Daxiao Sun (), Yanchang Li, Jinpei Zhang, Shiyu Liu, Dachuan Zhang, Jingxiang Zheng, Qing Xi, Haisha Liang, Wenkang Zhao, Ying Li, Mengbo Xu, Jiayu He, Tong Liu, Ayshamgul Hasim, Meisheng Ma, Ping Xu () and Na Mi ()
Additional contact information
Xuezhao Feng: The First Affiliated Hospital of Xinjiang Medical University
Daxiao Sun: Max Planck Institute of Molecular Cell Biology and Genetics
Yanchang Li: Beijing Proteome Research Center, Institute of Lifeomics
Jinpei Zhang: The First Affiliated Hospital of Xinjiang Medical University
Shiyu Liu: The First Affiliated Hospital of Xinjiang Medical University
Dachuan Zhang: Tsinghua University
Jingxiang Zheng: Tsinghua University
Qing Xi: The First Affiliated Hospital of Xinjiang Medical University
Haisha Liang: Tsinghua University
Wenkang Zhao: Tsinghua University
Ying Li: Tsinghua University
Mengbo Xu: The First Affiliated Hospital of Xinjiang Medical University
Jiayu He: The First Affiliated Hospital of Xinjiang Medical University
Tong Liu: The First Affiliated Hospital of Xinjiang Medical University
Ayshamgul Hasim: Xinjiang Medical University
Meisheng Ma: Tongji Medical College of Huazhong University of Science and Technology
Ping Xu: Beijing Proteome Research Center, Institute of Lifeomics
Na Mi: The First Affiliated Hospital of Xinjiang Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body plays pivotal roles during autophagosome formation, however, the underlying mechanisms are still not fully understood. Here we describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation. Mass spectrometry-based proteomics reveals significant enrichment of vesicle trafficking components within p62 body. Combining cellular experiments and biochemical reconstitution assays, we confirm the gathering of ATG9 and ATG16L1-positive vesicles around p62 body, especially in Atg2ab DKO cells with blocked lipid transfer and vesicle fusion. Interestingly, p62 body also regulates ATG9 and ATG16L vesicle trafficking flux intracellularly. We further determine the lipid contents associated with p62 body via lipidomic profiling. Moreover, with in vitro kinase assay, we uncover the functions of p62 body as a platform to assemble ULK1 complex and invigorate PI3KC3-C1 kinase cascade for PI3P generation. Collectively, our study raises a membrane-based working model for multifaceted p62 body in controlling autophagosome biogenesis, and highlights the interplay between membraneless condensates and membrane vesicles in regulating cellular functions.

Date: 2023
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DOI: 10.1038/s41467-023-42829-8

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