Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy

Through a quantitative proteomics analysis, a cohort of proteins is identified that associate with autophagosomes, among them a new cargo receptor called NCOA4 that, in response to iron deprivation, targets ferritin to autophagosomes and thereby releases iron. In selective autophagy, specific molecules known as cargo receptors bind to cargo molecules and target them to autophagosomes — vesicles that subsequently fuse with the cellular organelles lysosomes for enzymatic degradation of their content. Only a handful of such cargo receptors have been well characterized. Through quantitative proteomics analysis, Alec Kimmelman and co-workers have identified a cohort of proteins that associate with autophagosomes, among them a new cargo receptor, nuclear receptor coactivator 4 (NCOA4). Intriguingly, when deprived of iron, NCOA4 targets ferritin to autophagosomes, thereby releasing iron from its ferritin stores. These findings not only represent a cell biology resource, but also have implications for understanding iron metabolism. 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 neurodegeneration1,2. 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 limited3. 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 species4 but is degraded via autophagy to release iron5,6 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.