ID HUNIN_HUMAN Reviewed; 24 AA. AC Q8IVG9; DT 27-SEP-2004, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 10-JUN-2026, entry version 128. DE RecName: Full=Humanin {ECO:0000303|PubMed:11371646}; DE AltName: Full=Humanin mitochondrial {ECO:0000303|PubMed:19477263}; DE Short=HNM {ECO:0000303|PubMed:19477263}; GN Name=MT-RNR2 {ECO:0000312|HGNC:HGNC:7471}; GN Synonyms=HN {ECO:0000303|PubMed:11371646}; OS Homo sapiens (Human). OG Mitochondrion. OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND MUTAGENESIS OF LEU-9. RC TISSUE=Brain; RX PubMed=11371646; DOI=10.1073/pnas.101133498; RA Hashimoto Y., Niikura T., Tajima H., Yasukawa T., Sudo H., Ito Y., Kita Y., RA Kawasumi M., Kouyama K., Doyu M., Sobue G., Koide T., Tsuji S., Lang J., RA Kurokawa K., Nashimoto I.; RT "A rescue factor abolishing neuronal cell death by a wide spectrum of RT familial Alzheimer's disease genes and Abeta."; RL Proc. Natl. Acad. Sci. U.S.A. 98:6336-6341(2001). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH IGFBP3, AND RP MUTAGENESIS OF PHE-6. RX PubMed=14561895; DOI=10.1073/pnas.2135111100; RA Ikonen M., Liu B., Hashimoto Y., Ma L., Lee K.W., Niikura T., Nishimoto I., RA Cohen P.; RT "Interaction between the Alzheimer's survival peptide humanin and insulin- RT like growth factor-binding protein 3 regulates cell survival and RT apoptosis."; RL Proc. Natl. Acad. Sci. U.S.A. 100:13042-13047(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP FUNCTION, AND MUTAGENESIS OF 1-MET-ALA-2; 1-MET--PRO-3; PRO-3; RP 4-ARG--MET-6; CYS-8; LEU-9; LEU-12; THR-13; SER-14; PRO-19; 19-PRO--ALA-24 RP AND 20-VAL--ALA-24. RX PubMed=11717357; DOI=10.1523/jneurosci.21-23-09235.2001; RA Hashimoto Y., Niikura T., Ito Y., Sudo H., Hata M., Arakawa E., Abe Y., RA Kita Y., Nishimoto I.; RT "Detailed characterization of neuroprotection by a rescue factor humanin RT against various Alzheimer's disease-relevant insults."; RL J. Neurosci. 21:9235-9245(2001). RN [5] RP FUNCTION. RX PubMed=12154011; DOI=10.1096/fj.02-0018fje; RA Caricasole A., Bruno V., Cappuccio I., Melchiorri D., Copani A., RA Nicoletti F.; RT "A novel rat gene encoding a Humanin-like peptide endowed with broad RT neuroprotective activity."; RL FASEB J. 16:1331-1333(2002). RN [6] RP EVIDENCE OF IN VIVO EXPRESSION, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=12009529; DOI=10.1016/s0304-3940(02)00199-4; RA Tajima H., Niikura T., Hashimoto Y., Ito Y., Kita Y., Terashita K., RA Yamazaki K., Koto A., Aiso S., Nishimoto I.; RT "Evidence for in vivo production of Humanin peptide, a neuroprotective RT factor against Alzheimer's disease-related insults."; RL Neurosci. Lett. 324:227-231(2002). RN [7] RP INTERACTION WITH TRIM11, AND SUBCELLULAR LOCATION. RX PubMed=12670303; DOI=10.1046/j.1460-9568.2003.02553.x; RA Niikura T., Hashimoto Y., Tajima H., Ishizaka M., Yamagishi Y., RA Kawasumi M., Nawa M., Terashita K., Aiso S., Nishimoto I.; RT "A tripartite motif protein TRIM11 binds and destabilizes Humanin, a RT neuroprotective peptide against Alzheimer's disease-relevant insults."; RL Eur. J. Neurosci. 17:1150-1158(2003). RN [8] RP FUNCTION, SUBUNIT, AND MUTAGENESIS OF SER-7 AND SER-14. RX PubMed=12787071; DOI=10.1046/j.1471-4159.2003.01797.x; RA Terashita K., Hashimoto Y., Niikura T., Tajima H., Yamagishi Y., RA Ishizaka M., Kawasumi M., Chiba T., Kanekura K., Yamada M., Nawa M., RA Kita Y., Aiso S., Nishimoto I.; RT "Two serine residues distinctly regulate the rescue function of Humanin, an RT inhibiting factor of Alzheimer's disease-related neurotoxicity: functional RT potentiation by isomerization and dimerization."; RL J. Neurochem. 85:1521-1538(2003). RN [9] RP FUNCTION, INTERACTION WITH BAX, AND MUTAGENESIS OF 1-MET--PHE-6; RP 18-LEU--ALA-24; CYS-8 AND LEU-9. RX PubMed=12732850; DOI=10.1038/nature01627; RA Guo B., Zhai D., Cabezas E., Welsh K., Nouraini S., Satterthwait A.C., RA Reed J.C.; RT "Humanin peptide suppresses apoptosis by interfering with Bax activation."; RL Nature 423:456-461(2003). RN [10] RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND MUTAGENESIS OF PRO-3; SER-7; RP CYS-8; LEU-9; LEU-10; LEU-11; LEU-12; THR-13; SER-14; PRO-19 AND VAL-20. RX PubMed=12860203; DOI=10.1016/s0196-9781(03)00106-2; RA Yamagishi Y., Hashimoto Y., Niikura T., Nishimoto I.; RT "Identification of essential amino acids in Humanin, a neuroprotective RT factor against Alzheimer's disease-relevant insults."; RL Peptides 24:585-595(2003). RN [11] RP FUNCTION, AND MUTAGENESIS OF SER-14. RX PubMed=15465011; DOI=10.1016/j.bbrc.2004.09.046; RA Harada M., Habata Y., Hosoya M., Nishi K., Fujii R., Kobayashi M., RA Hinuma S.; RT "N-Formylated humanin activates both formyl peptide receptor-like 1 and RT 2."; RL Biochem. Biophys. Res. Commun. 324:255-261(2004). RN [12] RP FUNCTION. RX PubMed=15153530; DOI=10.4049/jimmunol.172.11.7078; RA Ying G., Iribarren P., Zhou Y., Gong W., Zhang N., Yu Z.-X., Le Y., Cui Y., RA Wang J.M.; RT "Humanin, a newly identified neuroprotective factor, uses the G protein- RT coupled formylpeptide receptor-like-1 as a functional receptor."; RL J. Immunol. 172:7078-7085(2004). RN [13] RP FUNCTION, INTERACTION WITH BID, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP CYS-8 AND SER-14. RX PubMed=15661737; DOI=10.1074/jbc.m411902200; RA Zhai D., Luciano F., Zhu X., Guo B., Satterthwait A.C., Reed J.C.; RT "Humanin binds and nullifies Bid activity by blocking its activation of Bax RT and Bak."; RL J. Biol. Chem. 280:15815-15824(2005). RN [14] RP FUNCTION, INTERACTION WITH BIM, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP CYS-8. RX PubMed=15661735; DOI=10.1074/jbc.m413062200; RA Luciano F., Zhai D., Zhu X., Bailly-Maitre B., Ricci J.E., RA Satterthwait A.C., Reed J.C.; RT "Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax RT family protein BimEL."; RL J. Biol. Chem. 280:15825-15835(2005). RN [15] RP FUNCTION. RX PubMed=16005025; DOI=10.1016/j.lfs.2005.03.031; RA Hashimoto Y., Suzuki H., Aiso S., Niikura T., Nishimoto I., Matsuoka M.; RT "Involvement of tyrosine kinases and STAT3 in Humanin-mediated RT neuroprotection."; RL Life Sci. 77:3092-3104(2005). RN [16] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=19477263; DOI=10.1016/j.ygeno.2009.05.006; RA Bodzioch M., Lapicka-Bodzioch K., Zapala B., Kamysz W., Kiec-Wilk B., RA Dembinska-Kiec A.; RT "Evidence for potential functionality of nuclearly-encoded humanin RT isoforms."; RL Genomics 94:247-256(2009). RN [17] RP FUNCTION. RX PubMed=19386761; DOI=10.1091/mbc.e09-02-0168; RA Hashimoto Y., Kurita M., Aiso S., Nishimoto I., Matsuoka M.; RT "Humanin inhibits neuronal cell death by interacting with a cytokine RT receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130."; RL Mol. Biol. Cell 20:2864-2873(2009). RN [18] RP FUNCTION, INTERACTION WITH IGFBP3, SUBCELLULAR LOCATION, DEVELOPMENTAL RP STAGE, AND MUTAGENESIS OF PHE-6 AND SER-7. RX PubMed=19623253; DOI=10.1371/journal.pone.0006334; RA Muzumdar R.H., Huffman D.M., Atzmon G., Buettner C., Cobb L.J., Fishman S., RA Budagov T., Cui L., Einstein F.H., Poduval A., Hwang D., Barzilai N., RA Cohen P.; RT "Humanin: a novel central regulator of peripheral insulin action."; RL PLoS ONE 4:e6334-e6334(2009). RN [19] RP FUNCTION. RX PubMed=19952275; DOI=10.1210/en.2009-0577; RA Lue Y., Swerdloff R., Liu Q., Mehta H., Hikim A.S., Lee K.W., Jia Y., RA Hwang D., Cobb L.J., Cohen P., Wang C.; RT "Opposing roles of insulin-like growth factor binding protein 3 and humanin RT in the regulation of testicular germ cell apoptosis."; RL Endocrinology 151:350-357(2010). RN [20] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=20542501; DOI=10.1016/j.fertnstert.2010.04.075; RA Moretti E., Giannerini V., Rossini L., Matsuoka M., Trabalzini L., RA Collodel G.; RT "Immunolocalization of humanin in human sperm and testis."; RL Fertil. Steril. 94:2888-2890(2010). RN [21] RP INTERACTION WITH MPP8. RX PubMed=23532874; DOI=10.1002/psc.2500; RA Maximov V.V., Martynenko A.V., Arman I.P., Tarantul V.Z.; RT "Humanin binds MPP8: mapping interaction sites of the peptide and RT protein."; RL J. Pept. Sci. 19:301-307(2013). RN [22] RP FUNCTION. RX PubMed=23277413; DOI=10.1007/s11064-012-0951-6; RA Zhao S.T., Zhao L., Li J.H.; RT "Neuroprotective Peptide humanin inhibits inflammatory response in RT astrocytes induced by lipopolysaccharide."; RL Neurochem. Res. 38:581-588(2013). RN [23] RP FUNCTION. RX PubMed=25138702; DOI=10.1007/s11010-014-2182-4; RA Hashimoto Y., Takeshita Y., Naito M., Uchino H., Matsuoka M.; RT "Apollon/Bruce is upregulated by Humanin."; RL Mol. Cell. Biochem. 397:147-155(2014). RN [24] RP FUNCTION, AND INTERACTION WITH IGFBP3. RX PubMed=26216267; DOI=10.2174/0929866522666150728114955; RA Njomen E., Evans H.G., Gedara S.H., Heyl D.L.; RT "Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 RT (IGFBP3) and Regulates Its Interaction with Importin-beta."; RL Protein Pept. Lett. 22:869-876(2015). RN [25] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=26990160; DOI=10.1167/iovs.15-17053; RA Sreekumar P.G., Ishikawa K., Spee C., Mehta H.H., Wan J., Yen K., Cohen P., RA Kannan R., Hinton D.R.; RT "The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From RT Oxidative Stress, Senescence, and Mitochondrial Dysfunction."; RL Invest. Ophthalmol. Vis. Sci. 57:1238-1253(2016). RN [26] RP FUNCTION. RX PubMed=27384491; DOI=10.18632/oncotarget.10380; RA Kim S.J., Guerrero N., Wassef G., Xiao J., Mehta H.H., Cohen P., Yen K.; RT "The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and RT STAT3 signaling pathways and has age-dependent signaling differences in the RT hippocampus."; RL Oncotarget 7:46899-46912(2016). RN [27] RP FUNCTION. RX PubMed=27783653; DOI=10.1371/journal.pone.0165150; RA Matsunaga D., Sreekumar P.G., Ishikawa K., Terasaki H., Barron E., RA Cohen P., Kannan R., Hinton D.R.; RT "Humanin Protects RPE Cells from Endoplasmic Reticulum Stress-Induced RT Apoptosis by Upregulation of Mitochondrial Glutathione."; RL PLoS ONE 11:e0165150-e0165150(2016). RN [28] RP FUNCTION, INTERACTION WITH AMYLOID-BETA PROTEIN 42, MASS SPECTROMETRY, AND RP MUTAGENESIS OF SER-14. RX PubMed=28282805; DOI=10.3233/jad-160951; RA Romeo M., Stravalaci M., Beeg M., Rossi A., Fiordaliso F., Corbelli A., RA Salmona M., Gobbi M., Cagnotto A., Diomede L.; RT "Humanin Specifically Interacts with Amyloid-beta Oligomers and Counteracts RT Their in vivo Toxicity."; RL J. Alzheimers Dis. 57:857-871(2017). RN [29] RP FUNCTION. RX PubMed=29432738; DOI=10.1016/j.bbrc.2018.02.071; RA Qin Q., Jin J., He F., Zheng Y., Li T., Zhang Y., He J.; RT "Humanin promotes mitochondrial biogenesis in pancreatic MIN6 beta-cells."; RL Biochem. Biophys. Res. Commun. 497:292-297(2018). RN [30] RP FUNCTION. RX PubMed=30029058; DOI=10.1016/j.molimm.2018.07.008; RA Wang X., Wu Z., He Y., Zhang H., Tian L., Zheng C., Shang T., Zhu Q., RA Li D., He Y.; RT "Humanin prevents high glucose-induced monocyte adhesion to endothelial RT cells by targeting KLF2."; RL Mol. Immunol. 101:245-250(2018). RN [31] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30920769; DOI=10.1111/andr.12614; RA Rao M., Wu Z., Wen Y., Wang R., Zhao S., Tang L.; RT "Humanin levels in human seminal plasma and spermatozoa are related to RT sperm quality."; RL Andrology 7:859-866(2019). RN [32] RP FUNCTION, AND MUTAGENESIS OF CYS-8 AND SER-14. RX PubMed=31690630; DOI=10.1074/jbc.ra119.011297; RA Morris D.L., Kastner D.W., Johnson S., Strub M.P., He Y., Bleck C.K.E., RA Lee D.Y., Tjandra N.; RT "Humanin induces conformational changes in the apoptosis regulator BAX and RT sequesters it into fibers, preventing mitochondrial outer-membrane RT permeabilization."; RL J. Biol. Chem. 294:19055-19065(2019). RN [33] RP FUNCTION. RX PubMed=32923762; DOI=10.1021/acsomega.0c01778; RA Li W., Zhang D., Yuan W., Wang C., Huang Q., Luo J.; RT "Humanin Ameliorates Free Fatty Acid-Induced Endothelial Inflammation by RT Suppressing the NLRP3 Inflammasome."; RL ACS Omega 5:22039-22045(2020). RN [34] RP FUNCTION, AND MUTAGENESIS OF CYS-8 AND SER-14. RX PubMed=33106313; DOI=10.1074/jbc.ra120.013023; RA Morris D.L., Johnson S., Bleck C.K.E., Lee D.Y., Tjandra N.; RT "Humanin selectively prevents the activation of pro-apoptotic protein BID RT by sequestering it into fibers."; RL J. Biol. Chem. 295:18226-18238(2020). RN [35] RP STRUCTURE BY NMR, AND DOMAIN. RX PubMed=15721287; DOI=10.1016/j.bbrc.2005.01.100; RA Benaki D., Zikos C., Evangelou A., Livaniou E., Vlassi M., Mikros E., RA Pelecanou M.; RT "Solution structure of humanin, a peptide against Alzheimer's disease- RT related neurotoxicity."; RL Biochem. Biophys. Res. Commun. 329:152-160(2005). RN [36] RP STRUCTURE BY NMR OF MUTANT GLY-14. RX PubMed=16945331; DOI=10.1016/j.bbrc.2006.08.087; RA Benaki D., Zikos C., Evangelou A., Livaniou E., Vlassi M., Mikros E., RA Pelecanou M.; RT "Solution structure of Ser14Gly-humanin, a potent rescue factor against RT neuronal cell death in Alzheimer's disease."; RL Biochem. Biophys. Res. Commun. 349:634-642(2006). RN [37] {ECO:0007744|PDB:5GIW} RP STRUCTURE BY NMR WITH D-SER-14, FUNCTION, AND MUTAGENESIS OF SER-14. RX PubMed=27349871; DOI=10.1016/j.bbrc.2016.06.114; RA Alsanousi N., Sugiki T., Furuita K., So M., Lee Y.H., Fujiwara T., RA Kojima C.; RT "Solution NMR structure and inhibitory effect against amyloid-beta RT fibrillation of Humanin containing a d-isomerized serine residue."; RL Biochem. Biophys. Res. Commun. 477:647-653(2016). CC -!- FUNCTION: Plays a role as a neuroprotective factor (PubMed:11371646, CC PubMed:11717357, PubMed:12154011, PubMed:12787071, PubMed:12860203, CC PubMed:19386761). Protects against neuronal cell death induced by CC multiple different familial Alzheimer disease genes and amyloid-beta CC proteins in Alzheimer disease (PubMed:11371646, PubMed:11717357, CC PubMed:12154011, PubMed:12787071, PubMed:12860203, PubMed:19386761). CC Mediates its neuroprotective effect by binding to the humanin receptor CC complex; binding of MT-RNR2 activates the intracellular JAK-STAT3 CC signaling pathways (PubMed:16005025, PubMed:19386761, PubMed:27384491). CC Also acts as a ligand for G protein-coupled receptors FPR2/FPRL1 and CC FPR3/FPRL2 (PubMed:15465011). Inhibits amyloid-beta protein 40 fibril CC formation (PubMed:27349871). Also inhibits amyloid-beta protein 42 CC fibril formation (PubMed:28282805). Suppresses apoptosis by binding to CC BAX and preventing the translocation of BAX from the cytosol to CC mitochondria (PubMed:12732850, PubMed:26990160). Also suppresses CC apoptosis by binding to BID and inhibiting the interaction of BID with CC BAX and BAK which prevents oligomerization of BAX and BAK and CC suppresses release of apoptogenic proteins from mitochondria CC (PubMed:15661737). Forms fibers with BAX and also with BID, inducing CC BAX and BID conformational changes and sequestering them into the CC fibers which prevents their activation (PubMed:31690630, CC PubMed:33106313). Can also suppress apoptosis by interacting with BIM CC isoform BimEL, inhibiting BimEL-induced activation of BAX, blocking CC oligomerization of BAX and BAK, and preventing release of apoptogenic CC proteins from mitochondria (PubMed:15661735). Plays a role in up- CC regulation of anti-apoptotic protein BIRC6/APOLLON, leading to CC inhibition of neuronal cell death (PubMed:25138702). Binds to IGFBP3 CC and specifically blocks IGFBP3-induced cell death (PubMed:14561895, CC PubMed:26216267). Competes with importin KPNB1 for binding to IGFBP3 CC which is likely to block IGFBP3 nuclear import (PubMed:26216267). CC Induces chemotaxis of mononuclear phagocytes via FPR2/FPRL1 CC (PubMed:15153530). Reduces aggregation and fibrillary formation by CC suppressing the effect of APP on mononuclear phagocytes and acts by CC competitively inhibiting the access of FPR2 to APP (PubMed:15153530). CC Protects retinal pigment epithelium (RPE) cells against oxidative CC stress-induced and endoplasmic reticulum (ER) stress-induced apoptosis CC (PubMed:26990160, PubMed:27783653). Promotes mitochondrial biogenesis CC in RPE cells following oxidative stress and promotes STAT3 CC phosphorylation which leads to inhibition of CASP3 release CC (PubMed:26990160). Also reduces CASP4 levels in RPE cells, suppresses CC ER stress-induced mitochondrial superoxide production and plays a role CC in up-regulation of mitochondrial glutathione (PubMed:27783653). CC Reduces testicular hormone deprivation-induced apoptosis of germ cells CC at the nonandrogen-sensitive stages of the seminiferous epithelium CC cycle (PubMed:19952275). Protects endothelial cells against free fatty CC acid-induced inflammation by suppressing oxidative stress, reducing CC expression of TXNIP and inhibiting activation of the NLRP3 inflammasome CC which inhibits expression of pro-inflammatory cytokines IL1B and IL18 CC (PubMed:32923762). Protects against high glucose-induced endothelial CC cell dysfunction by mediating activation of ERK5 which leads to CC increased expression of transcription factor KLF2 and prevents monocyte CC adhesion to endothelial cells (PubMed:30029058). Inhibits the CC inflammatory response in astrocytes (PubMed:23277413). Increases the CC expression of PPARGC1A/PGC1A in pancreatic beta cells which promotes CC mitochondrial biogenesis (PubMed:29432738). Increases insulin CC sensitivity (PubMed:19623253). {ECO:0000269|PubMed:11371646, CC ECO:0000269|PubMed:11717357, ECO:0000269|PubMed:12154011, CC ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:12787071, CC ECO:0000269|PubMed:12860203, ECO:0000269|PubMed:14561895, CC ECO:0000269|PubMed:15153530, ECO:0000269|PubMed:15465011, CC ECO:0000269|PubMed:15661735, ECO:0000269|PubMed:15661737, CC ECO:0000269|PubMed:16005025, ECO:0000269|PubMed:19386761, CC ECO:0000269|PubMed:19623253, ECO:0000269|PubMed:19952275, CC ECO:0000269|PubMed:23277413, ECO:0000269|PubMed:25138702, CC ECO:0000269|PubMed:26216267, ECO:0000269|PubMed:26990160, CC ECO:0000269|PubMed:27349871, ECO:0000269|PubMed:27384491, CC ECO:0000269|PubMed:27783653, ECO:0000269|PubMed:28282805, CC ECO:0000269|PubMed:29432738, ECO:0000269|PubMed:30029058, CC ECO:0000269|PubMed:31690630, ECO:0000269|PubMed:32923762, CC ECO:0000269|PubMed:33106313}. CC -!- SUBUNIT: Homodimer (PubMed:12787071, PubMed:12860203). Interacts with CC amyloid-beta protein 42 (Abeta42); the interaction prevents Abeta42 CC fibril formation (PubMed:28282805). Interacts with BAX; forms fibers CC with BAX which results in BAX conformational changes and sequestering CC of BAX into the fibers, preventing BAX activation (PubMed:12732850, CC PubMed:31690630). Interacts with both full-length BID and cleaved BID CC p15; forms fibers with BID which results in BID conformational changes CC and sequestering of BID into the fibers, preventing BID activation CC (PubMed:15661737, PubMed:33106313). Interacts with BIM isoform BimEL CC but not with BIM isoforms BimL or BimS; the interaction prevents BIM- CC induced apoptosis (PubMed:15661735). Interacts with IGFBP3; competes CC with importin KPNB1 for binding to IGFBP3, blocking IGFBP3 nuclear CC import (PubMed:14561895, PubMed:19623253, PubMed:26216267). Interacts CC with TRIM11 (PubMed:12670303). Interacts with MPP8 (PubMed:23532874). CC {ECO:0000269|PubMed:12670303, ECO:0000269|PubMed:12732850, CC ECO:0000269|PubMed:12787071, ECO:0000269|PubMed:12860203, CC ECO:0000269|PubMed:14561895, ECO:0000269|PubMed:15661735, CC ECO:0000269|PubMed:15661737, ECO:0000269|PubMed:19623253, CC ECO:0000269|PubMed:23532874, ECO:0000269|PubMed:26216267, CC ECO:0000269|PubMed:28282805, ECO:0000269|PubMed:31690630, CC ECO:0000269|PubMed:33106313}. CC -!- INTERACTION: CC Q8IVG9; PRO_0000000092 [P05067]: APP; NbExp=4; IntAct=EBI-8643752, EBI-821758; CC Q8IVG9; Q07812: BAX; NbExp=5; IntAct=EBI-8643752, EBI-516580; CC Q8IVG9; P17936: IGFBP3; NbExp=7; IntAct=EBI-8643752, EBI-715709; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11371646, CC ECO:0000269|PubMed:12860203, ECO:0000269|PubMed:19623253, CC ECO:0000269|PubMed:26990160}. Cytoplasm {ECO:0000269|PubMed:11371646, CC ECO:0000269|PubMed:12670303, ECO:0000269|PubMed:15661737, CC ECO:0000269|PubMed:20542501, ECO:0000269|PubMed:26990160}. Cell CC projection, cilium, flagellum {ECO:0000269|PubMed:20542501, CC ECO:0000269|PubMed:30920769}. Nucleus {ECO:0000269|PubMed:20542501}. CC Mitochondrion {ECO:0000269|PubMed:20542501, CC ECO:0000269|PubMed:26990160}. Note=Localizes to the sperm flagellum CC where it is highly concentrated in the midpiece (PubMed:20542501, CC PubMed:30920769). Detected in the cytoplasm and nucleus of CC spermatocytes and spermatids (PubMed:20542501). Also detected in sperm CC mitochondria (PubMed:20542501). In retinal pigment epithelium cells, CC detected in cytoplasm and mitochondria (PubMed:26990160). CC {ECO:0000269|PubMed:20542501, ECO:0000269|PubMed:26990160, CC ECO:0000269|PubMed:30920769}. CC -!- TISSUE SPECIFICITY: Expressed in testis, seminal plasma and sperm (at CC protein level) (PubMed:20542501, PubMed:30920769). Higher seminal CC plasma levels are associated with normospermia than with oligospermia, CC asthenospermia or oligoasthenospermia (at protein level) CC (PubMed:30920769). Higher sperm levels are associated with normospermia CC than with asthenospermia (at protein level) (PubMed:30920769). CC Expressed in retinal epithelial cells (at protein level) CC (PubMed:26990160). Expressed in the heart, skeletal muscle, kidney and CC liver. Lesser but significant expression is observed in the brain and CC the gastrointestinal tract. Expressed in the AD brain, where it is CC found in some of the large intact neurons of the occipital lobes and CC small and round reactive glial cells in the hippocampus. CC {ECO:0000269|PubMed:11371646, ECO:0000269|PubMed:12009529, CC ECO:0000269|PubMed:19477263, ECO:0000269|PubMed:20542501, CC ECO:0000269|PubMed:26990160, ECO:0000269|PubMed:30920769}. CC -!- DEVELOPMENTAL STAGE: Levels decline with increasing age. CC {ECO:0000269|PubMed:19623253}. CC -!- INDUCTION: Release is regulated by intracellular mechanism. The CC intracellular level is regulated by TRIM11 through proteasome-mediated CC degradation. {ECO:0000269|PubMed:19477263}. CC -!- DOMAIN: Largely unstructured in aqueous solution. CC {ECO:0000269|PubMed:15721287}. CC -!- MASS SPECTROMETRY: Mass=2686.78; Method=MALDI; CC Evidence={ECO:0000269|PubMed:28282805}; CC -!- SIMILARITY: Belongs to the humanin family. {ECO:0000305}. CC -!- CAUTION: The humanin peptide described here has been shown to be CC biologically active but is the product of a mitochondrial gene, MT-RNR2 CC (PubMed:12009529). If translation of the mRNA occurs in the CC mitochondrion rather than in the cytoplasm, then the usage of the CC mitochondrial genetic code would lead to the production of a shorter CC peptide lacking the last three C-terminal residues. The mechanisms CC allowing the production and the secretion of humanin remain unclear. CC The possibility exists that the physiologically active humanin peptide CC is encoded by one of the related genes present in the nuclear genome CC (PubMed:19477263). {ECO:0000305|PubMed:12009529, CC ECO:0000305|PubMed:19477263}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY029066; AAK50430.1; -; mRNA. DR EMBL; BE899497; -; NOT_ANNOTATED_CDS; mRNA. DR PDB; 1Y32; NMR; -; A=1-24. DR PDB; 2GD3; NMR; -; A=1-24. DR PDB; 5GIW; NMR; -; X=1-24. DR PDB; 7WVX; EM; 2.80 A; L=1-24. DR PDBsum; 1Y32; -. DR PDBsum; 2GD3; -. DR PDBsum; 5GIW; -. DR PDBsum; 7WVX; -. DR AlphaFoldDB; Q8IVG9; -. DR BMRB; Q8IVG9; -. DR EMDB; EMD-32861; -. DR SMR; Q8IVG9; -. DR FunCoup; Q8IVG9; 5. DR IntAct; Q8IVG9; 3. DR MINT; Q8IVG9; -. DR NDEx; IQUERY-CP-MT-RNR2; 1 NDEx IQuery Curated Pathway. DR iPTMnet; Q8IVG9; -. DR PhosphoSitePlus; Q8IVG9; -. DR BioMuta; HGNC:7471; -. DR AGR; HGNC:7471; -. DR GeneCards; MT-RNR2; -. DR HGNC; HGNC:7471; MT-RNR2. DR MalaCards; MT-RNR2; -. DR MIM; 561010; gene. DR InParanoid; Q8IVG9; -. DR PAN-GO; Q8IVG9; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q8IVG9; -. DR PathwayCommons; Q8IVG9; -. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR Reactome; R-HSA-444473; Formyl peptide receptors bind formyl peptides and many other ligands. DR SignaLink; Q8IVG9; -. DR ChiTaRS; MT-RNR2; human. DR EvolutionaryTrace; Q8IVG9; -. DR Pharos; Q8IVG9; Tdark. DR PRO; PR:Q8IVG9; -. DR Proteomes; UP000005640; Mitochondrion MT. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0036126; C:sperm flagellum; IDA:UniProtKB. DR GO; GO:0097225; C:sperm midpiece; IDA:UniProtKB. DR GO; GO:0001664; F:G protein-coupled receptor binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0048019; F:receptor antagonist activity; IDA:UniProtKB. DR GO; GO:0048018; F:receptor ligand activity; IDA:UniProt. DR GO; GO:0005102; F:signaling receptor binding; TAS:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0097696; P:cell surface receptor signaling pathway via STAT; IDA:UniProtKB. DR GO; GO:0007267; P:cell-cell signaling; IDA:UniProtKB. DR GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProtKB. DR GO; GO:0006879; P:intracellular iron ion homeostasis; NAS:UniProtKB. DR GO; GO:0030595; P:leukocyte chemotaxis; IDA:UniProtKB. DR GO; GO:0007005; P:mitochondrion organization; IDA:UniProtKB. DR GO; GO:1905907; P:negative regulation of amyloid fibril formation; IDA:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:1900118; P:negative regulation of execution phase of apoptosis; IBA:GO_Central. DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:UniProtKB. DR GO; GO:0032692; P:negative regulation of interleukin-1 production; IDA:UniProtKB. DR GO; GO:0032701; P:negative regulation of interleukin-18 production; IDA:UniProtKB. DR GO; GO:0150079; P:negative regulation of neuroinflammatory response; IDA:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:UniProtKB. DR GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IDA:UniProtKB. DR GO; GO:1902883; P:negative regulation of response to oxidative stress; IDA:UniProtKB. DR GO; GO:0097435; P:supramolecular fiber organization; IDA:UniProtKB. DR CDD; cd20245; humanin; 1. DR DisProt; DP02267; -. DR InterPro; IPR028139; Humanin. DR PANTHER; PTHR33895; HUMANIN-LIKE 4; 1. DR PANTHER; PTHR33895:SF15; HUMANIN-RELATED; 1. DR Pfam; PF15040; Humanin; 1. PE 1: Evidence at protein level; KW 3D-structure; Apoptosis; Cell projection; Cilium; Cytoplasm; Flagellum; KW Mitochondrion; Nucleus; Reference proteome; Secreted. FT CHAIN 1..24 FT /note="Humanin" FT /id="PRO_0000044146" FT REGION 1..12 FT /note="Sufficient to interact with BID and BIM and to FT suppress BID and BIM activity" FT /evidence="ECO:0000269|PubMed:15661735, FT ECO:0000269|PubMed:15661737" FT REGION 3..19 FT /note="Sufficient for neuroprotective activity" FT REGION 5..12 FT /note="Sufficient to interact with MPP8" FT /evidence="ECO:0000269|PubMed:23532874" FT REGION 9..11 FT /note="Required for secretion" FT /evidence="ECO:0000269|PubMed:12860203" FT REGION 19..20 FT /note="Required for secretion" FT /evidence="ECO:0000269|PubMed:12860203" FT MUTAGEN 1..6 FT /note="Missing: No effect on binding to BAX." FT /evidence="ECO:0000269|PubMed:12732850" FT MUTAGEN 1..3 FT /note="Missing: Abolishes neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357" FT MUTAGEN 1..2 FT /note="Missing: No effect on neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357" FT MUTAGEN 3 FT /note="P->A: Abolishes neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12860203" FT MUTAGEN 4..6 FT /note="RGF->AGA: Potentiates neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357" FT MUTAGEN 6 FT /note="F->A: Abolishes binding to IGFBP3 and increases FT insulin sensitivity." FT /evidence="ECO:0000269|PubMed:14561895, FT ECO:0000269|PubMed:19623253" FT MUTAGEN 7 FT /note="S->A: Abolishes neuroprotective activity and FT dimerization. No effect on insulin sensitivity." FT /evidence="ECO:0000269|PubMed:12787071, FT ECO:0000269|PubMed:12860203, ECO:0000269|PubMed:19623253" FT MUTAGEN 8 FT /note="C->A: Abolishes neuroprotective activity. Formation FT of short irregularly shaped fibers with BAX with fibers FT showing non-uniform diameters. Formation of thin FT irregularly kinked fibers with BID." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:12860203, FT ECO:0000269|PubMed:31690630, ECO:0000269|PubMed:33106313" FT MUTAGEN 8 FT /note="C->D,E,F,G,I,L,M,N,Q,S,T,V,W,Y: Abolishes FT neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12732850" FT MUTAGEN 8 FT /note="C->H: Significantly reduces neuroprotective FT activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12732850" FT MUTAGEN 8 FT /note="C->K,R: No effect on neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12732850" FT MUTAGEN 8 FT /note="C->P: Abolishes neuroprotective activity and FT interaction with BAX and BID. Abolishes BID-induced caspase FT activation and mitochondrial release of SMAC. Greatly FT reduced interaction with BIM. Abolishes BIM-induced caspase FT activation and apoptosis." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:15661735, FT ECO:0000269|PubMed:15661737" FT MUTAGEN 9 FT /note="L->A: Abolishes neuroprotective activity and FT dimerization." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:12860203" FT MUTAGEN 9 FT /note="L->R: Abolishes binding to BAX. Abolishes FT secretion." FT /evidence="ECO:0000269|PubMed:11371646, FT ECO:0000269|PubMed:11717357, ECO:0000269|PubMed:12732850, FT ECO:0000269|PubMed:12860203" FT MUTAGEN 10 FT /note="L->D: Abolishes secretion." FT /evidence="ECO:0000269|PubMed:12860203" FT MUTAGEN 10 FT /note="L->R: Abolishes secretion." FT /evidence="ECO:0000269|PubMed:12860203" FT MUTAGEN 11 FT /note="L->R: Abolishes secretion." FT /evidence="ECO:0000269|PubMed:12860203" FT MUTAGEN 12 FT /note="L->A: Abolishes neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12860203" FT MUTAGEN 13 FT /note="T->A: Abolishes neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12860203" FT MUTAGEN 14 FT /note="S->A,R,W,E,P: Abolishes neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12787071, ECO:0000269|PubMed:12860203" FT MUTAGEN 14 FT /note="S->G: Potentiates neuroprotective activity. FT Increased inhibition of amyloid-beta protein 40 fibril FT formation. Reduced levels of amyloid-beta 42 protein. FT Affects fiber formation with BAX with fewer fibers running FT in parallel. Affects fiber formation with BID with FT formation of shorter fibers. No effect on binding to BID or FT on BID-induced caspase activation and mitochondrial release FT of SMAC. Does not affect interaction with FPR2 or FPR3." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:15465011, ECO:0000269|PubMed:15661737, FT ECO:0000269|PubMed:27349871, ECO:0000269|PubMed:28282805, FT ECO:0000269|PubMed:31690630, ECO:0000269|PubMed:33106313" FT MUTAGEN 19..24 FT /note="Missing: Abolishes neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357" FT MUTAGEN 19 FT /note="P->A: Abolishes neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357, FT ECO:0000269|PubMed:12860203" FT MUTAGEN 19 FT /note="P->R: Abolishes secretion." FT /evidence="ECO:0000269|PubMed:12860203" FT MUTAGEN 20..24 FT /note="Missing: No effect on neuroprotective activity." FT /evidence="ECO:0000269|PubMed:11717357" FT MUTAGEN 20 FT /note="V->R: Abolishes secretion." FT /evidence="ECO:0000269|PubMed:12860203" FT STRAND 5..10 FT /evidence="ECO:0007829|PDB:7WVX" FT STRAND 14..17 FT /evidence="ECO:0007829|PDB:2GD3" FT STRAND 18..21 FT /evidence="ECO:0007829|PDB:1Y32" SQ SEQUENCE 24 AA; 2687 MW; 08B9A778EC13B971 CRC64; MAPRGFSCLL LLTSEIDLPV KRRA //