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. Animal studies show that iron is not efficiently moving from ferritin stores and orthochromatic erythroblast apoptosis is enhanced in iron-deficient models. Studies on cultured cells and zebrafish also implicate NCOA4 inerythroid devlopsment nd intracellular iron availability. Lack of NCOA4 additionally was linked to higher susceptibility to iron overload. It was shown that when mice was fed with diet supplemented with iron, those deficient NCOA4 has shown much increase of oxidative stress, liver damages and survivorship.
Regulation of ferritinophagy Intracellular iron status regulates NCOA4-dependent ferritinophagy. When intracellular iron is plentiful, NCOA4 is ubiquitinated by the ubiquitin ligase HERC2, proteasomally degraded, thus diminishing turnover and increasing storage of intracellular iron in ferritin. Conversely, during low intracellular iron level, there is less binding to HERC2, resulting in elevated levels of NCOA4, increasing turnover and release of stored iron in ferritin. NCOA4 directly binds the heavy chain of the ferritin through a conserved C-terminal domain and this binding is required for ferritinophagy and intracellular iron pool.
Role in disease Disregulation in iron homeostasis and autophagy have further research in NCOA4-mediated ferritinophagy during neurodegenerative diseases. It is mentioned in review articles about the possible associations of NCOA4 defects, oxidative stress, ferroptosis, AD, and PD, though they have yet to demonstrate causality. Modified ferritinophagy and atypical iron accumulation has also been implicated in oxidative stress and neuron cell death in some neurodegenerative conditions. Since NCOA4 is involved in the regulation of turnover and cytoplasmic iron supply, it has been suggested as a potential component of networks underlying neurodegeneration and ferroptosis.
Interactions NCOA4 has been shown to interact with:
Androgen receptor, and Peroxisome proliferator-activated receptor gamma Ferritin ATG8
See also Transcription coregulator
References
Further reading
External links NURSA C92 This article incorporates text from the United States National Library of Medicine, which is in the public domain.
