Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy

By J. Mancias, Xiaoxu Wang, Steven P. Gygi, J. Harper, Alec C. Kimmelman. Nature, 2014

1,845 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Epidemiology, Hematology

View Paper: https://www.semanticscholar.org/paper/50d2fc5bcf77dc5bd588ad14f14f350d070d415f

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Citations in the corpus

Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis (2019, background): “In addition, a higher level of iron transport proteins increased iron-mediated ROS and subsequently led to ferroptosis [134, 135].”
Molecular definitions of autophagy and related processes (2017, positive): “…2015), zymophagy (targeting zymogen granules in pancreatic acinar cells) (Grasso et al , 2011), granulophagy (targeting stress granules) (Buchan et al , 2013), and ferritinophagy (targeting ferritin via the receptor nuclear receptor coactivator 4, NCOA4) (Dowdle et al , 2014; Mancias et al , 2014).”
Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease (2015, background): “NCOA4 knockdown also resulted in an increase in IRP2 and TfR1 [30], likely from a decrease in labile iron owing to ferritin protein accumulation.”
The Roles of NRF2 in Modulating Cellular Iron Homeostasis (2017, background): “In times of iron deficiency, the iron reservoir within ferritin proteins can be liberated through ferritinophagy (90, 91).”
Autophagy-Independent Functions of the Autophagy Machinery (2019, background): “Such necroptotic response is exacerbated, rather than blunted, by chemical inhibitors of lysosomal degradation (Goodall et al., 2016), pointing to a non-autophagic role for ATG5, ATG7, and VPS34 in this setting.”
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “266 Ataxia telangiectasia mutated (ATM) phosphorylates NCOA4 to enhance ferritinophagy, promoting ferroptosis by increasing intracellular labile iron.”
Recent insights into the function of autophagy in cancer (2016, background): “…mitochondria to link with the autophagy cargo receptors OPTN andNDP52, ferritin is recognized by a new adaptor (NCOA4), which localizes to autophagosomes and is required for delivery of ferritin to the lysosome, where iron is released for use by the cell (Dowdle et al. 2014; Mancias et al. 2014).”
Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors. (2020, background): “NCOA4 interacts with ATG8s but does not contain a canonical LIR motif.”