Abstract
NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4-FTH1 interaction, we demonstrate that direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes. Moreover, NCOA4 abundance is under dual control via autophagy and the ubiquitin proteasome system. Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. In zebrafish and cultured cells, NCOA4 plays an essential role in erythroid differentiation. This work reveals the molecular nature of the NCOA4-ferritin complex and explains how intracellular iron levels modulate NCOA4-mediated ferritinophagy in cells and in an iron-dependent physiological setting.
Highlights
Iron is essential for the survival of most organisms as it serves as a cofactor for a host of biochemical processes including oxygen storage, oxidative phosphorylation, and enzymatic reactions required for cellular proliferation (Pantopoulos et al, 2012)
Given that NCOA4 levels appear to control flux through the ferritinophagy pathway, what mechanisms control the abundance of NCOA4? We previously reported that NCOA4 levels are altered by intracellular iron status (Mancias et al, 2014); when iron levels are high, NCOA4 abundance is low, thereby promoting ferritin accumulation and iron capture
This interaction appears to be present basally in all cells examined suggesting that some basal level of ferritinophagy is necessary to maintain iron homeostasis under standard tissue culture conditions
Summary
Iron is essential for the survival of most organisms as it serves as a cofactor for a host of biochemical processes including oxygen storage, oxidative phosphorylation, and enzymatic reactions required for cellular proliferation (Pantopoulos et al, 2012). The levels of free iron in a cell must be tightly controlled to avoid the generation of reactive oxygen species (ROS) via the Fenton reaction (Dixon and Stockwell, 2014). The cell has evolved mechanisms whereby iron can be sequestered and released from protein complexes in response to changing iron levels (Anderson et al, 2012). One such protein is ferritin, which forms a complex of 24 subunits (consisting of a mixture of ferritin heavy and light chains, FTH1 and FTL, respectively) capable of storing up to 4500 iron atoms (Arosio et al, 2009). Ferritin is degraded in the lysosome and recent evidence implicated autophagy, a conserved catabolic cellular pathway, in the ‘ferritinophagy’
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