Humanin

Definition:

Plays a role as a neuroprotective factor. Protects against neuronal cell death induced by multiple different familial Alzheimer disease genes and amyloid-beta proteins in Alzheimer disease. Mediates its neuroprotective effect by interacting with a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR. Also acts as a ligand for G-protein coupled receptors FPR2/FPRL1 and FPR3/FPRL2. Inhibits amyloid-beta protein 40 fibril formation. Also inhibits amyloid-beta protein 42 fibril formation. Suppresses apoptosis by binding to BAX and preventing the translocation of BAX from the cytosol to mitochondria. Also suppresses apoptosis by binding to BID and inhibiting the interaction of BID with BAX and BAK which prevents oligomerization of BAX and BAK and suppresses release of apoptogenic proteins from mitochondria. Forms fibers with BAX and also with BID, inducing BAX and BID conformational changes and sequestering them into the fibers which prevents their activation. Can also suppress apoptosis by interacting with BIM isoform BimEL, inhibiting BimEL-induced activation of BAX, blocking oligomerization of BAX and BAK, and preventing release of apoptogenic proteins from mitochondria. Plays a role in up-regulation of anti-apoptotic protein BIRC6/APOLLON, leading to inhibition of neuronal cell death. Binds to IGFBP3 and specifically blocks IGFBP3-induced cell death. Competes with importin KPNB1 for binding to IGFBP3 which is likely to block IGFBP3 nuclear import. Induces chemotaxis of mononuclear phagocytes via FPR2/FPRL1. Reduces aggregation and fibrillary formation by suppressing the effect of APP on mononuclear phagocytes and acts by competitively inhibiting the access of FPR2 to APP. Protects retinal pigment epithelium (RPE) cells against oxidative stress-induced and endoplasmic reticulum (ER) stress-induced apoptosis. Promotes mitochondrial biogenesis in RPE cells following oxidative stress and promotes STAT3 phosphorylation which leads to inhibition of CASP3 release. Also reduces CASP4 levels in RPE cells, suppresses ER stress-induced mitochondrial superoxide production and plays a role in up-regulation of mitochondrial glutathione. Reduces testicular hormone deprivation-induced apoptosis of germ cells at the nonandrogen-sensitive stages of the seminiferous epithelium cycle. Protects endothelial cells against free fatty acid-induced inflammation by suppressing oxidative stress, reducing expression of TXNIP and inhibiting activation of the NLRP3 inflammasome which inhibits expression of pro-inflammatory cytokines IL1B and IL18. Protects against high glucose-induced endothelial cell dysfunction by mediating activation of ERK5 which leads to increased expression of transcription factor KLF2 and prevents monocyte adhesion to endothelial cells. Inhibits the inflammatory response in astrocytes. Increases the expression of PPARGC1A/PGC1A in pancreatic beta cells which promotes mitochondrial biogenesis. Increases insulin sensitivity.

References:

[1]. Kenzo Terashita, et al. Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease-related neurotoxicity: functional potentiation by isomerization and dimerization. J Neurochem. 2003 Jun;85(6):1521-38. [Content Brief]

[2]. Yuichi Hashimoto, et al. Apollon/Bruce is upregulated by Humanin. Mol Cell Biochem. 2014 Dec;397(1-2):147-55. [Content Brief]

[3]. Radhika H Muzumdar, et al. Humanin: a novel central regulator of peripheral insulin action. PLoS One. 2009 Jul 22;4(7):e6334. [Content Brief]

[4]. Bin Guo, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003 May 22;423(6938):456-61. [Content Brief]

[5]. Dayong Zhai, et al. Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak. J Biol Chem. 2005 Apr 22;280(16):15815-24. [Content Brief]

[6]. Qingqing Qin, et al. Humanin promotes mitochondrial biogenesis in pancreatic MIN6 β-cells. Biochem Biophys Res Commun. 2018 Feb 26;497(1):292-297. [Content Brief]

[7]. Masataka Harada, et al. N-Formylated humanin activates both formyl peptide receptor-like 1 and 2. Biochem Biophys Res Commun. 2004 Nov 5;324(1):255-61. [Content Brief]

[8]. Xiaohui Wang, et al. Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2. Mol Immunol. 2018 Sep;101:245-250. [Content Brief]

[9]. Andrea Caricasole, et al. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity. FASEB J. 2002 Aug;16(10):1331-3. [Content Brief]

[10]. Margherita Romeo, et al. Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity. J Alzheimers Dis. 2017;57(3):857-871. [Content Brief]

[11]. Frederic Luciano, et al. Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL. J Biol Chem. 2005 Apr 22;280(16):15825-35. [Content Brief]

[12]. Shen-Ting Zhao, et al. Neuroprotective Peptide humanin inhibits inflammatory response in astrocytes induced by lipopolysaccharide. Neurochem Res. 2013 Mar;38(3):581-8. [Content Brief]

[13]. Wenfeng Li, et al. Humanin Ameliorates Free Fatty Acid-Induced Endothelial Inflammation by Suppressing the NLRP3 Inflammasome. ACS Omega. 2020 Aug 26;5(35):22039-22045. [Content Brief]

[14]. Daniel L Morris, et al. Humanin selectively prevents the activation of pro-apoptotic protein BID by sequestering it into fibers. J Biol Chem. 2020 Dec 25;295(52):18226-18238. [Content Brief]

[15]. Yohichi Yamagishi, et al. Identification of essential amino acids in Humanin, a neuroprotective factor against Alzheimer's disease-relevant insults. Peptides. 2003 Apr;24(4):585-95. [Content Brief]

[16]. YanHe Lue, et al. Opposing roles of insulin-like growth factor binding protein 3 and humanin in the regulation of testicular germ cell apoptosis. Endocrinology. 2010 Jan;151(1):350-7. [Content Brief]

[17]. Y Hashimoto, et al. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults. J Neurosci. 2001 Dec 1;21(23):9235-45. [Content Brief]

[18]. Evert Njomen, et al. Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and Regulates Its Interaction with Importin-β. Protein Pept Lett. 2015;22(10):869-76. [Content Brief]

[19]. Y Hashimoto, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336-41. [Content Brief]

[20]. Douglas Matsunaga, et al. Humanin Protects RPE Cells from Endoplasmic Reticulum Stress-Induced Apoptosis by Upregulation of Mitochondrial Glutathione. PLoS One. 2016 Oct 26;11(10):e0165150. [Content Brief]

[21]. Guoguang Ying, et al. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. J Immunol. 2004 Jun 1;172(11):7078-85. [Content Brief]

[22]. Yuichi Hashimoto, et al. Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Mol Biol Cell. 2009 Jun;20(12):2864-73. [Content Brief]

[23]. Nesreen Alsanousi, et al. Solution NMR structure and inhibitory effect against amyloid-β fibrillation of Humanin containing a d-isomerized serine residue. Biochem Biophys Res Commun. 2016 Sep 2;477(4):647-653. [Content Brief]

[24]. Parameswaran G Sreekumar, et al. The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1238-53. [Content Brief]

[25]. Maaria Ikonen, et al. Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13042-7. [Content Brief]

[26]. Daniel L Morris, et al. Humanin induces conformational changes in the apoptosis regulator BAX and sequesters it into fibers, preventing mitochondrial outer-membrane permeabilization. J Biol Chem. 2019 Dec 13;294(50):19055-19065. [Content Brief]

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