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Network organization of the human autophagy system.

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.

SUBMITTER: Behrends C

PROVIDER: S-EPMC2901998 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Network organization of the human autophagy system.

Behrends Christian C Sowa Mathew E ME Gygi Steven P SP Harper J Wade JW

Nature 20100620 7302

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 ...[more]

PMID: 20562859

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Project description:Radiation therapy (RT) plays a vital role in the treatment of brain cancers, but it frequently results in cognitive decline in the patients who receive it. Because the underlying mechanisms for this decline remain poorly understood, the brain is typically treated as a single, uniform volume when evaluating the toxic effects of RT plans. This ignorance represents a significant deficit in the field of radiation oncology, as the technology exists to manipulate dose distributions to spare regions of the brain, but there exists no body of knowledge regarding what is critical to spare. This deficit exists due to the numerous confounding factors that are frequently associated with radiotherapy, including the tumors themselves, other treatments such as surgery and chemotherapy, and dose gradients across the brain. Here, we present a case in which a 57-year-old male patient received a uniform dose of radiation across the whole brain, did not receive concurrent chemotherapy, had minimal surgical intervention and a small tumor burden, and received resting-state functional magnetic resonance imaging (fMRI) scans both before and after RT. To our knowledge, this is the first study on the effects of whole-brain radiotherapy on functional network organization, and this patient's treatment regimen represents a rare and non-replicable opportunity to isolate the effects of radiation on functional connectivity. We observed substantial changes in the subject's behavior and functional network organization over a 12-month timeframe. Interestingly, the homogenous radiation dose to the brain had a heterogeneous effect on cortical networks, and the functional networks most affected correspond with observed cognitive behavioral deficits. This novel study suggests that the cognitive decline that occurs after whole-brain radiation therapy may be network specific and related to the disruption of large-scale distributed functional systems, and it indicates that fMRI is a promising avenue of study for optimizing cognitive outcomes after RT.

Dataset Information

Network organization of the human autophagy system.

Publications

Network organization of the human autophagy system.

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