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Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.

Nature | May 1, 2014

Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration. Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo, including organelles, proteins or intracellular pathogens, are targeted for selective autophagy is limited. Here we use quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins in human cells, including cargo receptors. Like known cargo receptors, nuclear receptor coactivator 4 (NCOA4) was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.

Pubmed ID: 24695223 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Autophagy | Autophagy-Related Protein 8 Family | Biological Availability | Ferritins | Homeostasis | Humans | Iron | Lysosomes | Microfilament Proteins | Nuclear Receptor Coactivators | Phagosomes | Protein Binding | Protein Transport | Proteomics | Substrate Specificity

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM095567
  • Agency: NIGMS NIH HHS, Id: GM070565
  • Agency: NCI NIH HHS, Id: R01 CA157490
  • Agency: NIGMS NIH HHS, Id: R01 GM095567
  • Agency: NCI NIH HHS, Id: R01CA157490
  • Agency: NIGMS NIH HHS, Id: R01 GM070565
  • Agency: NCI NIH HHS, Id: P50 CA127003

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