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Network organization of the human autophagy system

Author

Listed:
  • Christian Behrends

    (Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Mathew E. Sowa

    (Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Steven P. Gygi

    (Harvard Medical School, Boston, Massachusetts 02115, USA)

  • J. Wade Harper

    (Harvard Medical School, Boston, Massachusetts 02115, USA)

Abstract

Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. Although conserved protein kinase, lipid kinase and ubiquitin-like protein conjugation subnetworks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here we report a proteomic analysis of the autophagy interaction network in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new autophagy interaction network components have roles in vesicle trafficking, protein or lipid phosphorylation and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The six ATG8 orthologues in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.

Suggested Citation

  • Christian Behrends & Mathew E. Sowa & Steven P. Gygi & J. Wade Harper, 2010. "Network organization of the human autophagy system," Nature, Nature, vol. 466(7302), pages 68-76, July.
  • Handle: RePEc:nat:nature:v:466:y:2010:i:7302:d:10.1038_nature09204
    DOI: 10.1038/nature09204
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    Cited by:

    1. Timothy C Matisziw & Tony H Grubesic & Junyu Guo, 2012. "Robustness Elasticity in Complex Networks," PLOS ONE, Public Library of Science, vol. 7(7), pages 1-10, July.
    2. Hong-Wen Tang & Kerstin Spirohn & Yanhui Hu & Tong Hao & István A. Kovács & Yue Gao & Richard Binari & Donghui Yang-Zhou & Kenneth H. Wan & Joel S. Bader & Dawit Balcha & Wenting Bian & Benjamin W. Bo, 2023. "Next-generation large-scale binary protein interaction network for Drosophila melanogaster," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Yu Guo & Minjie Shen & Qiping Dong & Natasha M. Méndez-Albelo & Sabrina X. Huang & Carissa L. Sirois & Jonathan Le & Meng Li & Ezra D. Jarzembowski & Keegan A. Schoeller & Michael E. Stockton & Vaness, 2023. "Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    4. Xiaoting Zhou & You-Kyung Lee & Xianting Li & Henry Kim & Carlos Sanchez-Priego & Xian Han & Haiyan Tan & Suiping Zhou & Yingxue Fu & Kerry Purtell & Qian Wang & Gay R. Holstein & Beisha Tang & Junmin, 2024. "Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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