NCOA4

Nuclear receptor coactivator 4, also known as Androgen Receptor Activator (ARA70), is a protein that in humans is encoded by the NCOA4 gene. It plays an important role in ferritinophagy, acting as a cargo receptor, binding to the ferritin heavy chain and latching on to ATG8 on the surface of the autophagosome. Research has also linked that NCOA4 to erythropoiesis, ferroptosis, and iron-related neurodegenrative disease pathway.

Function

NCOA4 functions as a selective cargo receptor involved in ferritinophagy, which is a form of selective autophagy responsible for ferritin degradation. NCOA4 binds ferritin heavy chain (FTH1) and delivers ferritin complexes to autophagosomes for lysosomal degration.Through regulation of ferritin turnover and intracellular iron presence, NCOA contributes to cellular iron homeostasis.

NCOA4 levels are controlled by intracellular iron concentration. Under high iron condition, NCOA4 interacts with the ubiquitin ligase HERC2 and undergoes proteasomal breakdown, lowering ferritonophagy activity.

Iron homeostasis

NCOA4 is involved in systemic iron homeostasis in a process called ferritinophagy, the autophagic clearance of ferritin, and has key roles in this process. NCOA4-deficient mouse models showed accumulation of ferritin in various organs like the spleen, liver, duodenum and bone marrow, indicative of defects in ferritin degradation. Tissue iron accumulation was found in these mice in addition to elavated serum ferritin levels, even though their intracellular iron steles to be c separated

Upon low iron intake, mice that don't have NCOA4 exhibit marked microcytic hypo chromic anemia and dyserythropoiesis with impaired provision of iron of Hb synthesis.