Recombinant Human Humanin (MT-RNR2)

Function

Plays a role as a neuroprotective factor (PubMed:11371646, PubMed:11717357, PubMed:12154011, PubMed:12787071, PubMed:12860203, PubMed:19386761). Protects against neuronal cell death induced by multiple different familial Alzheimer disease genes and amyloid-beta proteins in Alzheimer disease (PubMed:11371646, PubMed:11717357, PubMed:12154011, PubMed:12787071, PubMed:12860203, PubMed:19386761). Mediates its neuroprotective effect by binding to the humanin receptor complex; binding of MT-RNR2 activates the intracellular JAK-STAT3 signaling pathways (PubMed:16005025, PubMed:19386761, PubMed:27384491). Also acts as a ligand for G protein-coupled receptors FPR2/FPRL1 and FPR3/FPRL2 (PubMed:15465011). Inhibits amyloid-beta protein 40 fibril formation (PubMed:27349871). Also inhibits amyloid-beta protein 42 fibril formation (PubMed:28282805). Suppresses apoptosis by binding to BAX and preventing the translocation of BAX from the cytosol to mitochondria (PubMed:12732850, PubMed:26990160). 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 (PubMed:15661737). Forms fibers with BAX and also with BID, inducing BAX and BID conformational changes and sequestering them into the fibers which prevents their activation (PubMed:31690630, PubMed:33106313). 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 (PubMed:15661735). Plays a role in up-regulation of anti-apoptotic protein BIRC6/APOLLON, leading to inhibition of neuronal cell death (PubMed:25138702). Binds to IGFBP3 and specifically blocks IGFBP3-induced cell death (PubMed:14561895, PubMed:26216267). Competes with importin KPNB1 for binding to IGFBP3 which is likely to block IGFBP3 nuclear import (PubMed:26216267). Induces chemotaxis of mononuclear phagocytes via FPR2/FPRL1 (PubMed:15153530). 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 (PubMed:15153530). Protects retinal pigment epithelium (RPE) cells against oxidative stress-induced and endoplasmic reticulum (ER) stress-induced apoptosis (PubMed:26990160, PubMed:27783653). Promotes mitochondrial biogenesis in RPE cells following oxidative stress and promotes STAT3 phosphorylation which leads to inhibition of CASP3 release (PubMed:26990160). Also reduces CASP4 levels in RPE cells, suppresses ER stress-induced mitochondrial superoxide production and plays a role in up-regulation of mitochondrial glutathione (PubMed:27783653). Reduces testicular hormone deprivation-induced apoptosis of germ cells at the nonandrogen-sensitive stages of the seminiferous epithelium cycle (PubMed:19952275). 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 (PubMed:32923762). 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 (PubMed:30029058). Inhibits the inflammatory response in astrocytes (PubMed:23277413). Increases the expression of PPARGC1A/PGC1A in pancreatic beta cells which promotes mitochondrial biogenesis (PubMed:29432738). Increases insulin sensitivity (PubMed:19623253)

Subcellular Location

Secreted; Cytoplasm; Cell projection, cilium, flagellum; Nucleus; Mitochondrion

Tissue Specificity

Expressed in testis, seminal plasma and sperm (at protein level) (PubMed:20542501, PubMed:30920769). Higher seminal plasma levels are associated with normospermia than with oligospermia, asthenospermia or oligoasthenospermia (at protein level) (PubMed:30920769). Higher sperm levels are associated with normospermia than with asthenospermia (at protein level) (PubMed:30920769). Expressed in retinal epithelial cells (at protein level) (PubMed:26990160). Expressed in the heart, skeletal muscle, kidney and liver. Lesser but significant expression is observed in the brain and the gastrointestinal tract. Expressed in the AD brain, where it is found in some of the large intact neurons of the occipital lobes and small and round reactive glial cells in the hippocampus

Subunit

Homodimer (PubMed:12787071, PubMed:12860203). Interacts with amyloid-beta protein 42 (Abeta42); the interaction prevents Abeta42 fibril formation (PubMed:28282805). Interacts with BAX; forms fibers with BAX which results in BAX conformational changes and sequestering of BAX into the fibers, preventing BAX activation (PubMed:12732850, PubMed:31690630). Interacts with both full-length BID and cleaved BID p15; forms fibers with BID which results in BID conformational changes and sequestering of BID into the fibers, preventing BID activation (PubMed:15661737, PubMed:33106313). Interacts with BIM isoform BimEL but not with BIM isoforms BimL or BimS; the interaction prevents BIM-induced apoptosis (PubMed:15661735). Interacts with IGFBP3; competes with importin KPNB1 for binding to IGFBP3, blocking IGFBP3 nuclear import (PubMed:14561895, PubMed:19623253, PubMed:26216267). Interacts with TRIM11 (PubMed:12670303). Interacts with MPP8 (PubMed:23532874)

• Hashimoto Y. 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)
• Ikonen M. 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)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Hashimoto Y. et al. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults. — J. Neurosci. (2001)
• Caricasole A. et al. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity. — FASEB J. (2002)
• Tajima H. et al. Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults. — Neurosci. Lett. (2002)
• Niikura T. et al. A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults. — Eur. J. Neurosci. (2003)
• Terashita K. 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)