NCOA4

NCOA4, or nuclear receptor coactivator 4, is a protein encoded by the NCOA4 gene. It is best known as a selective autophagy receptor that mediates ferritinophagy, the autophagic degradation of ferritin, thereby regulating intracellular iron homeostasis. In addition to its role in ferritinophagy, NCOA4 is related to the broader family of nuclear receptor coactivators, reflecting its original characterization as a transcriptional coactivator in other contexts.

Function and mechanism

NCOA4 binds ferritin and directs ferritin-containing cargo to autophagosomes by interacting with LC3, a component of the autophagy machinery. This ferritinophagy process delivers ferritin to lysosomes, where ferritin is degraded and iron is released into the cytosol. The flux of iron from ferritin influences the cellular labile iron pool and supports iron-requiring processes. NCOA4 contains motifs that enable ferritin binding as well as an LC3-interacting region to recruit autophagosomes.

Regulation

NCOA4 activity is sensitive to cellular iron status. Under iron-replete conditions, NCOA4 can be ubiquitinated and degraded, reducing ferritinophagy. When iron is scarce, NCOA4 is stabilized, promoting ferritin degradation to free iron. Components of the ubiquitin-proteasome system and related regulators modulate this balance to maintain iron homeostasis.

Clinical and biological significance

Through ferritinophagy, NCOA4 influences iron availability, ferroptosis sensitivity, and cellular responses to iron stress. Dysregulation of NCOA4-mediated ferritinophagy has been implicated in disorders of iron metabolism and in cancer cell iron handling, highlighting its role in iron recycling and metabolic adaptation.

History

The ferritinophagy role of NCOA4 was described in the mid-2010s, establishing NCOA4 as a key cargo receptor directing ferritin degradation via autophagy.