Biology:NCOA4

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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 presense, 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 ferritinophay. When intracellular iron is plentiful, NCOA4 is ubquitonated by the ubiquitin ligase HERC2, proteasomal 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

Further reading

• "The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2". Genes, Chromosomes & Cancer 11 (1): 51–57. September 1994. doi:10.1002/gcc.2870110108. PMID 7529046. 
• "Development of a single-step duplex RT-PCR detecting different forms of ret activation, and identification of the third form of in vivo ret activation in human papillary thyroid carcinoma". Cancer Letters 78 (1–3): 69–76. April 1994. doi:10.1016/0304-3835(94)90033-7. PMID 8180971. 
• "Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas". Cancer Research 54 (11): 2979–2985. June 1994. PMID 8187085. 
• "Comparison of the breakpoint regions of ELE1 and RET genes involved in the generation of RET/PTC3 oncogene in sporadic and in radiation-associated papillary thyroid carcinomas". Genomics 42 (2): 252–259. June 1997. doi:10.1006/geno.1997.4685. PMID 9192845. 
• "Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells". Proceedings of the National Academy of Sciences of the United States of America 95 (13): 7379–7384. June 1998. doi:10.1073/pnas.95.13.7379. PMID 9636157. Bibcode: 1998PNAS...95.7379M. 
• "Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform". Molecular Endocrinology 13 (1): 117–128. January 1999. doi:10.1210/mend.13.1.0214. PMID 9892017. 
• "Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor". The Journal of Biological Chemistry 274 (13): 8570–8576. March 1999. doi:10.1074/jbc.274.13.8570. PMID 10085091. 
• "From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells". Proceedings of the National Academy of Sciences of the United States of America 96 (10): 5458–5463. May 1999. doi:10.1073/pnas.96.10.5458. PMID 10318905. Bibcode: 1999PNAS...96.5458Y. 
• "Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma". The Journal of Biological Chemistry 274 (23): 16147–16152. June 1999. doi:10.1074/jbc.274.23.16147. PMID 10347167. 
• "RFG (ARA70, ELE1) interacts with the human androgen receptor in a ligand-dependent fashion, but functions only weakly as a coactivator in cotransfection assays". Molecular Endocrinology 13 (10): 1645–1656. October 1999. doi:10.1210/mend.13.10.0352. PMID 10517667. 
• "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–1795. November 2000. doi:10.1101/gr.143000. PMID 11076863. 
• "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports 1 (3): 287–292. September 2000. doi:10.1093/embo-reports/kvd058. PMID 11256614. 
• "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor". Proceedings of the National Academy of Sciences of the United States of America 98 (13): 7200–7205. June 2001. doi:10.1073/pnas.121173298. PMID 11404460. Bibcode: 2001PNAS...98.7200L. 
• "Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma". The American Journal of Pathology 160 (1): 247–254. January 2002. doi:10.1016/S0002-9440(10)64368-4. PMID 11786418. 
• "Domain interactions between coregulator ARA(70) and the androgen receptor (AR)". Molecular Endocrinology 16 (2): 287–300. February 2002. doi:10.1210/mend.16.2.0765. PMID 11818501. 
• "Mutations in the helix 3 region of the androgen receptor abrogate ARA70 promotion of 17beta-estradiol-induced androgen receptor transactivation". The Journal of Biological Chemistry 277 (39): 36499–36508. September 2002. doi:10.1074/jbc.M202824200. PMID 12068007. 

External links

• NURSA C92

This article incorporates text from the United States National Library of Medicine, which is in the public domain.