Humanin

The humanin gene is found within the 16S rRNA gene (MT-RNR2) in the mitochondrial genome

Humanin is a peptide[1] that is encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2.[2] Its structure contains a three-turn a-helix, and no symmetry.[1]

The length of the peptide depends on where it is produced. If it is produced inside the mitochondria it will be 21 amino acids long.[3] If it is produced outside the mitochondria, in the cytosol, it will be 24 amino acids long.[3] Both peptides have been shown to have biological activity.[3][4]


Humanin was independently discovered by three labs looking at Alzheimer's disease, apoptosis, and IGF-1 signaling.[2][4][5]

Experiments using cultured cells have demonstrated that humanin has both neuroprotective as well as cytoprotective effects and experiments in rodents have found that it has protective effects in Alzheimer's disease models, Huntington's disease models and stroke models (reviewed in [6] ).

Discovery

Humanin was independently found by three different labs looking at different parameters. The first to publish was the Nishimoto lab in 2001 where they found humanin while looking for possible proteins that could protect cells from amyloid beta, a major component of Alzheimer's disease.[2] The Reed lab found humanin in a screen looking for proteins that could interact with Bcl-2-associated X protein (Bax), a major protein involved in apoptosis.[4] The Cohen lab (Pinchas Cohen) independently discovered humanin when screening for proteins that interact with IGFBP3.[5]

Protective Effects

Humanin is proposed to have myriad neuroprotective and cytoprotective effects. Both studies in cells and rodents have both found that administration of humanin or humanin derivatives increases survival and/or physiological parameters in Alzheimer's disease models.[7][8] In addition to Alzheimer's disease, humanin has other neuroprotective effects against models of Huntington's disease, prion disease, and stroke.[9][10][11] Beyond the possible neuroprotective effects, humanin protects against oxidative stress, atherosclerotic plaque formation, and heart attack.[12][13][14][15] Metabolic effects have also been demonstrated and humanin helps improve survival of pancreatic beta-cells, which may help with type 1 diabetes,[16] and increases insulin sensitivity, which may help with type 2 diabetes.[17]

Mechanism of Action

The beneficial effects of humanin have been proposed to have several different modes of action. Extracellular interaction with a tripartite receptor composed of gp130, WSX1, and CNTFR, as well as interaction with the formyl peptide receptor 2 (formylpeptide-like-1 receptor) have been published.[18][19] Intracellular interaction with BAX, tBID, IGFBP3, and TRIM11 may also be required for the effects of humanin.[4][5][20][21]

Homologs

The rat, Rattus norvegicus, has a gene, rattin, that encodes a 38 amino acid peptide, which is homologous to humanin.[22] The two genes produce cDNAs that show 88% sequence identity.[22] The peptides are 81% identical, with the carboxyl terminal sequence 14 amino acids longer in rattin.[22] Of the 24 amino acids in the rest of the sequence, 20 are the identical.[22]

Rattin shows the same ability as humanin to defend neurons from the toxicity of beta-amyloid, the cause of degeneration in Alzheimer's Disease.[22]

References

  1. 1 2 http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=1Y32
  2. 1 2 3 Hashimoto, Y; Niikura, T; Tajima, H; Yasukawa, T; Sudo, H; Ito, Y; Kita, Y; Kawasumi, M; Kouyama, K; Doyu, M; Sobue, G; Koide, T; Tsuji, S; Lang, J; Kurokawa, K; Nishimoto, I (May 22, 2001). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America 98 (11): 6336–41. doi:10.1073/pnas.101133498. PMC: 33469. PMID 11371646. Cite uses deprecated parameter |coauthors= (help)
  3. 1 2 3 Yen, Kelvin; Lee, Changhan; Mehta, Hemal; Cohen, Pinchas (Feb 1, 2013) [2013]. "The emerging role of the mitochondrial-derived peptide humanin in stress resistance". Journal of Molecular Endocrinology (Bioscientifica, published Feb 2013) 50 (1 pages=R11-R19). doi:10.1530/JME-12-0203. ISSN 0952-5041. PMC: 3705736. PMID 23239898.
  4. 1 2 3 4 Guo, B; Zhai, D; Cabezas, E; Welsh, K; Nouraini, S; Satterthwait, AC; Reed, JC (May 22, 2003). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature 423 (6938): 456–61. doi:10.1038/nature01627. PMID 12732850.
  5. 1 2 3 Ikonen, M; Liu, B; Hashimoto, Y; Ma, L; Lee, KW; Niikura, T; Nishimoto, I; Cohen, P (Oct 28, 2003). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America 100 (22): 13042–7. doi:10.1073/pnas.2135111100. PMC: 240741. PMID 14561895.
  6. ↑ Yen, K; Lee, C; Mehta, H; Cohen, P (Feb 2013). "The emerging role of the mitochondrial-derived peptide humanin in stress resistance". Journal of molecular endocrinology 50 (1): R11–9. doi:10.1530/JME-12-0203. PMC: 3705736. PMID 23239898.
  7. ↑ Tajima, H; Kawasumi, M; Chiba, T; Yamada, M; Yamashita, K; Nawa, M; Kita, Y; Kouyama, K; Aiso, S; Matsuoka, M; Niikura, T; Nishimoto, I (Mar 1, 2005). "A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice". Journal of neuroscience research 79 (5): 714–23. doi:10.1002/jnr.20391. PMID 15678515.
  8. ↑ Hashimoto, Y; Niikura, T; Ito, Y; Sudo, H; Hata, M; Arakawa, E; Abe, Y; Kita, Y; Nishimoto, I (Dec 1, 2001). "Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults". The Journal of neuroscience : the official journal of the Society for Neuroscience 21 (23): 9235–45. PMID 11717357.
  9. ↑ Kariya, S; Hirano, M; Nagai, Y; Furiya, Y; Fujikake, N; Toda, T; Ueno, S (2005). "Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches". Journal of molecular neuroscience : MN 25 (2): 165–9. doi:10.1385/JMN:25:2:165. PMID 15784964.
  10. ↑ Sponne, I; Fifre, A; Koziel, V; Kriem, B; Oster, T; Pillot, T (Jan 2004). "Humanin rescues cortical neurons from prion-peptide-induced apoptosis". Molecular and cellular neurosciences 25 (1): 95–102. doi:10.1016/j.mcn.2003.09.017. PMID 14962743.
  11. ↑ Xu, X; Chua, CC; Gao, J; Hamdy, RC; Chua, BH (Oct 2006). "Humanin is a novel neuroprotective agent against stroke". Stroke; a journal of cerebral circulation 37 (10): 2613–9. doi:10.1161/01.STR.0000242772.94277.1f. PMID 16960089.
  12. ↑ Bachar, AR; Scheffer, L; Schroeder, AS; Nakamura, HK; Cobb, LJ; Oh, YK; Lerman, LO; Pagano, RE; Cohen, P; Lerman, A (Nov 1, 2010). "Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress". Cardiovascular research 88 (2): 360–6. doi:10.1093/cvr/cvq191. PMC: 2952532. PMID 20562421.
  13. ↑ Oh, YK; Bachar, AR; Zacharias, DG; Kim, SG; Wan, J; Cobb, LJ; Lerman, LO; Cohen, P; Lerman, A (Nov 2011). "Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice". Atherosclerosis 219 (1): 65–73. doi:10.1016/j.atherosclerosis.2011.06.038. PMC: 3885346. PMID 21763658.
  14. ↑ Zacharias, DG; Kim, SG; Massat, AE; Bachar, AR; Oh, YK; Herrmann, J; Rodriguez-Porcel, M; Cohen, P; Lerman, LO; Lerman, A (2012). Westermark, Per, ed. "Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans". PLoS ONE 7 (2): e31065. doi:10.1371/journal.pone.0031065. PMC: 3273477. PMID 22328926.
  15. ↑ Muzumdar, RH; Huffman, DM; Calvert, JW; Jha, S; Weinberg, Y; Cui, L; Nemkal, A; Atzmon, G; Klein, L; Gundewar, S; Ji, SY; Lavu, M; Predmore, BL; Lefer, DJ (Oct 2010). "Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice". Arteriosclerosis, thrombosis, and vascular biology 30 (10): 1940–8. doi:10.1161/ATVBAHA.110.205997. PMC: 2941397. PMID 20651283.
  16. ↑ Hoang, PT; Park, P; Cobb, LJ; Paharkova-Vatchkova, V; Hakimi, M; Cohen, P; Lee, KW (Mar 2010). "The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice". Metabolism: clinical and experimental 59 (3): 343–9. doi:10.1016/j.metabol.2009.08.001. PMC: 2932671. PMID 19800083.
  17. ↑ Muzumdar, RH; Huffman, DM; Atzmon, G; Buettner, C; Cobb, LJ; Fishman, S; Budagov, T; Cui, L; Einstein, FH; Poduval, A; Hwang, D; Barzilai, N; Cohen, P (Jul 22, 2009). Vella, Adrian, ed. "Humanin: a novel central regulator of peripheral insulin action". PLoS ONE 4 (7): e6334. doi:10.1371/journal.pone.0006334. PMC: 2709436. PMID 19623253.
  18. ↑ Hashimoto, Y; Kurita, M; Aiso, S; Nishimoto, I; Matsuoka, M (Jun 2009). "Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130". Molecular Biology of the Cell 20 (12): 2864–73. doi:10.1091/mbc.E09-02-0168. PMC: 2695794. PMID 19386761.
  19. ↑ Ying, G; Iribarren, P; Zhou, Y; Gong, W; Zhang, N; Yu, ZX; Le, Y; Cui, Y; Wang, JM (Jun 1, 2004). "Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor". Journal of immunology (Baltimore, Md. : 1950) 172 (11): 7078–85. doi:10.4049/jimmunol.172.11.7078. PMID 15153530.
  20. ↑ Zhai, D; Luciano, F; Zhu, X; Guo, B; Satterthwait, AC; Reed, JC (Apr 22, 2005). "Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak". The Journal of Biological Chemistry 280 (16): 15815–24. doi:10.1074/jbc.M411902200. PMID 15661737.
  21. ↑ Niikura, T; Hashimoto, Y; Tajima, H; Ishizaka, M; Yamagishi, Y; Kawasumi, M; Nawa, M; Terashita, K; Aiso, S; Nishimoto, I (Mar 2003). "A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults". The European Journal of Neuroscience 17 (6): 1150–8. doi:10.1046/j.1460-9568.2003.02553.x. PMID 12670303.
  22. 1 2 3 4 5 Caricasole, Andrea; Bruno, Valerian; Cappuccio, Irene; Melchiorri, Daniela; Copani, Agata; Nicoletti, Ferdinando (August 2002) [2002]. "A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity" (PDF). The FASEB Journal (The Federation of American Societies for Experimental Biology) 16 (10): 1331–1333. doi:10.1096/fj.02-0018fj. ISSN 0892-6638. Retrieved July 7, 2014.
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