HUNIN_HUMAN
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 03-AUG-2022, entry version 114.
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 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 [16]
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 [17]
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 [18]
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 [19]
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 [20]
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 [21]
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 [22]
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 [23]
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 [24]
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 [25]
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 [26]
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 [27]
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 [28]
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 [29]
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 [30]
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 [31]
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 [32]
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 [33]
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 [34]
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 [35] {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:12860203, PubMed:19386761, PubMed:12787071,
CC PubMed:12154011). 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:12860203, PubMed:19386761, PubMed:12787071, PubMed:12154011).
CC Mediates its neuroprotective effect by interacting with a receptor
CC complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR
CC (PubMed:19386761). Also acts as a ligand for G-protein coupled
CC receptors FPR2/FPRL1 and FPR3/FPRL2 (PubMed:15465011). Inhibits
CC amyloid-beta protein 40 fibril formation (PubMed:27349871). Also
CC inhibits amyloid-beta protein 42 fibril formation (PubMed:28282805).
CC Suppresses apoptosis by binding to BAX and preventing the translocation
CC of BAX from the cytosol to mitochondria (PubMed:12732850,
CC PubMed:26990160). Also suppresses apoptosis by binding to BID and
CC inhibiting the interaction of BID with BAX and BAK which prevents
CC oligomerization of BAX and BAK and suppresses release of apoptogenic
CC proteins from mitochondria (PubMed:15661737). Forms fibers with BAX and
CC also with BID, inducing BAX and BID conformational changes and
CC sequestering them into the fibers which prevents their activation
CC (PubMed:31690630, PubMed:33106313). Can also suppress apoptosis by
CC interacting with BIM isoform BimEL, inhibiting BimEL-induced activation
CC of BAX, blocking oligomerization of BAX and BAK, and preventing release
CC of apoptogenic proteins from mitochondria (PubMed:15661735). Plays a
CC role in up-regulation of anti-apoptotic protein BIRC6/APOLLON, leading
CC to 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:19386761, ECO:0000269|PubMed:19623253,
CC ECO:0000269|PubMed:19952275, ECO:0000269|PubMed:23277413,
CC ECO:0000269|PubMed:25138702, ECO:0000269|PubMed:26216267,
CC ECO:0000269|PubMed:26990160, ECO:0000269|PubMed:27349871,
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 SMR; Q8IVG9; -.
DR IntAct; Q8IVG9; 3.
DR MINT; Q8IVG9; -.
DR iPTMnet; Q8IVG9; -.
DR PhosphoSitePlus; Q8IVG9; -.
DR BioMuta; HGNC:7471; -.
DR PRIDE; Q8IVG9; -.
DR GeneCards; MT-RNR2; -.
DR HGNC; HGNC:7471; MT-RNR2.
DR MIM; 606120; gene.
DR neXtProt; NX_Q8IVG9; -.
DR Orphanet; 155; NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy.
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.
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:0043621; F:protein self-association; IDA:UniProtKB.
DR GO; GO:0048019; F:receptor antagonist activity; IDA:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; TAS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0006879; P:cellular iron ion homeostasis; NAS:UniProtKB.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IDA: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:1901215; P:negative regulation of neuron death; 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; PTHR33895; 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 HELIX 4..15
FT /evidence="ECO:0007829|PDB:1Y32"
FT STRAND 18..21
FT /evidence="ECO:0007829|PDB:1Y32"
SQ SEQUENCE 24 AA; 2687 MW; 08B9A778EC13B971 CRC64;
MAPRGFSCLL LLTSEIDLPV KRRA
