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Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.

Nature (2014-04-04)
Joseph D Mancias, Xiaoxu Wang, Steven P Gygi, J Wade Harper, Alec C Kimmelman
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ferritin from equine spleen, Type I, saline solution
Sigma-Aldrich
Iron, chips, 99.98% trace metals basis
Sigma-Aldrich
Ferritin from human spleen, Type V, 10 μg/mL in 0.15 M NaCl, 10 mM Tris, pH 8.0, containing 0.1% sodium azide
Sigma-Aldrich
Iron, foil, thickness 0.1 mm, ≥99.9% trace metals basis
Sigma-Aldrich
Iron, wire, diam. 0.5 mm, ≥99.9% trace metals basis
Sigma-Aldrich
Iron, powder, −325 mesh, 97%
Sigma-Aldrich
Iron, rod, diam. 6.3 mm, 99.98% trace metals basis
Sigma-Aldrich
Iron, puriss. p.a., carbonyl-Iron powder, low in magnesium and manganese compounds, ≥99.5% (RT)
Iron, IRMM®, certified reference material, 0.5 mm wire
Iron, rod, 1000mm, diameter 25mm, as drawn, 98+%
Iron, foil, 150x150mm, thickness 0.125mm, hard, 99.5%
Iron, foil, not light tested, 50x50mm, thickness 0.009mm, 99.85%
Iron, rod, 200mm, diameter 50mm, as drawn, armcO« soft ingot 99.8%
Iron, foil, 50x50mm, thickness 0.25mm, as rolled, 99.99+%
Iron, tube, 200mm, outside diameter 12.0mm, inside diameter 9mm, wall thickness 1.5mm, annealed, 99.5%
Iron, foil, not light tested, 50x50mm, thickness 0.0025mm, 99.85%
Iron, foil, 300x300mm, thickness 1.0mm, as rolled, armco« soft ingot 99.8%
Iron, tube, 100mm, outside diameter 6.35mm, inside diameter 5.35mm, wall thickness 0.5mm, as drawn, 99.8%
Iron, rod, 50mm, diameter 12.7mm, as drawn, 99.95%
Iron, rod, 100mm, diameter 5.0mm, as drawn, 99.99+%
Iron, tube, 100mm, outside diameter 1.0mm, inside diameter 0.8mm, wall thickness 0.1mm, as drawn, 99.5%
Iron, foil, 25x25mm, thickness 0.125mm, as rolled, 99.99+%
Iron, rod, 500mm, diameter 19mm, as drawn, soft ingot 99.8%
Iron, rod, 50mm, diameter 40mm, as drawn, armcO« soft ingot 99.8%
Iron, tube, 200mm, outside diameter 6.35mm, inside diameter 5.35mm, wall thickness 0.5mm, as drawn, 99.8%
Iron, foil, 10mm disks, thickness 0.008mm, 99.85%
Iron, foil, 0.5m coil, thickness 0.038mm, hard, 99.5%
Iron, foil, 300x300mm, thickness 0.125mm, hard, 99.5%
Iron, foil, 25x25mm, thickness 0.9mm, as rolled, 99.5%
Iron, foil, 150x150mm, thickness 0.5mm, hard, 99.5%