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NCOA4

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NCOA4
Identifiers
AliasesNCOA4, ARA70, ELE1, PTC3, RFG, nuclear receptor coactivator 4
External IDsOMIM: 601984; MGI: 1350932; HomoloGene: 38052; GeneCards: NCOA4; OMA:NCOA4 - orthologs
Available structures
PDBHuman UniProt search: PDBe RCSB
Orthologs
SpeciesHumanMouse
Entrez

8031

27057

Ensembl

ENSG00000266412

ENSMUSG00000056234

UniProt

Q13772

n/a

RefSeq (mRNA)

NM_005437
NM_001145260
NM_001145261
NM_001145262
NM_001145263

NM_001033988
NM_001284319
NM_019744

RefSeq (protein)

NP_001138732
NP_001138733
NP_001138734
NP_001138735
NP_005428

n/a

Location (UCSC)Chr 10: 46.01 – 46.03 MbChr 14: 31.88 – 31.9 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nuclear receptor coactivator 4, also known as Androgen Receptor Activator (ARA70), is a protein that in humans is encoded by the NCOA4 gene.[5][6][7] 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.[8][9]

Function

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NCOA4 functions as a selective cargo receptor involved in ferritinophagy, which is a form of selective autophagy responsible for ferritin degradation.[8] NCOA4 binds ferritin heavy chain (FTH1) and delivers ferritin complexes to autophagosomes for lysosomal degration.[9]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.[9]

Iron homeostasis

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NCOA4 is involved in systemic iron homeostasis in a process called ferritinophagy, the autophagic clearance of ferritin, and has key roles in this process.[10] 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.[10] 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[10]

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.[10] Animal studies show that iron is not efficiently moving from ferritin stores and orthochromatic erythroblast apoptosis is enhanced in iron-deficient models. [10] Studies on cultured cells and zebrafish also implicate NCOA4 inerythroid devlopsment nd intracellular iron availability. [9]

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. [10]

Regulation of ferritinophagy

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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. [11]

Role in disease

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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. [8] 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.[8]

Interactions

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NCOA4 has been shown to interact with:

See also

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References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000266412 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000056234 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, et al. (February 1994). "Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma". Oncogene. 9 (2): 509–516. PMID 8290261.
  6. 1 2 Yeh S, Chang C (May 1996). "Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5517–5521. Bibcode:1996PNAS...93.5517Y. doi:10.1073/pnas.93.11.5517. PMC 39278. PMID 8643607.
  7. ↑ "Entrez Gene: NCOA4 Nuclear receptor coactivator 4".
  8. 1 2 3 4 Quiles Del Rey M, Mancias JD (2019-03-14). "NCOA4-Mediated Ferritinophagy: A Potential Link to Neurodegeneration". Frontiers in Neuroscience. 13: 238. doi:10.3389/fnins.2019.00238. PMC 6427834. PMID 30930742.
  9. 1 2 3 4 Mancias JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X, et al. (October 2015). "Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis". eLife. 4 e10308. doi:10.7554/eLife.10308. PMC 4592949. PMID 26436293.
  10. 1 2 3 4 5 6 7 Bellelli R, Federico G, Matte' A, Colecchia D, Iolascon A, Chiariello M, et al. (January 2016). "NCOA4 Deficiency Impairs Systemic Iron Homeostasis". Cell Reports. 14 (3): 411–421. doi:10.1016/j.celrep.2015.12.065. PMID 26776506.
  11. 1 2 Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC (May 2014). "Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy". Nature. 509 (7498): 105–109. Bibcode:2014Natur.509..105M. doi:10.1038/nature13148. PMC 4180099. PMID 24695223.
  12. ↑ Alen P, Claessens F, Schoenmakers E, Swinnen JV, Verhoeven G, Rombauts W, et al. (January 1999). "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. doi:10.1210/mend.13.1.0214. PMID 9892017.
  13. ↑ Miyamoto H, Yeh S, Wilding G, Chang C (June 1998). "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. Bibcode:1998PNAS...95.7379M. doi:10.1073/pnas.95.13.7379. PMC 22623. PMID 9636157.
  14. ↑ Lin HK, Yeh S, Kang HY, Chang C (June 2001). "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. Bibcode:2001PNAS...98.7200L. doi:10.1073/pnas.121173298. PMC 34646. PMID 11404460.
  15. ↑ Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C (May 1999). "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. Bibcode:1999PNAS...96.5458Y. doi:10.1073/pnas.96.10.5458. PMC 21881. PMID 10318905.
  16. ↑ Zhou ZX, He B, Hall SH, Wilson EM, French FS (February 2002). "Domain interactions between coregulator ARA(70) and the androgen receptor (AR)". Molecular Endocrinology. 16 (2): 287–300. doi:10.1210/mend.16.2.0765. PMID 11818501.
  17. ↑ He B, Minges JT, Lee LW, Wilson EM (March 2002). "The FXXLF motif mediates androgen receptor-specific interactions with coregulators". The Journal of Biological Chemistry. 277 (12): 10226–10235. doi:10.1074/jbc.M111975200. PMID 11779876.
  18. ↑ Gao T, Brantley K, Bolu E, McPhaul MJ (October 1999). "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. doi:10.1210/mend.13.10.0352. PMID 10517667.
  19. ↑ He B, Wilson EM (March 2003). "Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs". Molecular and Cellular Biology. 23 (6): 2135–2150. doi:10.1128/mcb.23.6.2135-2150.2003. PMC 149467. PMID 12612084.
  20. ↑ Heinlein CA, Ting HJ, Yeh S, Chang C (June 1999). "Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma". The Journal of Biological Chemistry. 274 (23): 16147–16152. doi:10.1074/jbc.274.23.16147. PMID 10347167.
  21. ↑ Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, et al. (November 2014). "Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo". Nature Cell Biology. 16 (11): 1069–1079. doi:10.1038/ncb3053. PMID 25327288. S2CID 21172670.

Further reading

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

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