Humanin (HN) is a 24 amino acid polypeptide (Met- Ala- Pro- Arg- Gly- Phe- Ser- Cys- Leu- Leu- Leu- Leu- Thr- Ser- Glu- Ile- Asp- Leu- Pro- Val- Lys- Arg- Arg- Ala; M.W. = 2656.3 Da) that was first identified from a cDNA library from the surviving neurons of human Alzheimer's disease (AD) brain
[1]. Since its initial discovery, several cDNAs sharing sequence homology to HN have been identified in plants, nematodes, and rodents demonstrating that HN is evolutionarily conserved
[2]. HN is transcribed from an open reading frame within the mitochondrial 16S ribosomal RNA. Endogenous HN is both an intracellular and secreted protein and has been detected in normal mouse testis and colon at specific stages of development
[3]. In addition to brain, colon and testis, we have shown the presence of HN by western blot in rodent heart, ovary, pancreas and kidney (unpublished data). In addition, our group has demonstrated the presence of HN in cerebral spinal fluid (CSF), seminal fluid and plasma, with levels in the biologically active range (Cohen & Hwang, unpublished data).
Despite little being known regarding the regulation of HN production
in vivo, the major role of HN is believed to be promoting cell survival. Indeed, HN has a well-described role in neuroprotection against cell death associated with AD
[1], from AD-specific insults
[4], prion induced apoptosis
[5] and chemically-induced neuronal damage
[6]. Interestingly, a highly-potent analogue of HN, termed HNG, (HN in which the serine at position 14 is replaced by glycine), reverses the learning and memory impairment induced by scopolamine in mice
[6] and also has rescue activity against memory impairment caused by AD-related insults
in vivo [7]. The protection of HN from AD-related cytotoxicity has also been demonstrated in non-neuronal cells such as cerebrovascular smooth muscle
[8], rat phaeochromocytoma cells and lymphocytes under serum-deprived conditions
[9].
The anti-apoptotic potential of HN appears to be dependent upon the formation of homodimers, as interfering with this process completely blocks its ability to suppress cell death
[10]. Once dimerized, HN directly interacts with a variety of pro-apoptotic proteins, including Bax-related proteins
[2] and insulin-like growth factor binding protein-3 (IGFBP-3)
[11]. It has been shown that HN protects against apoptosis by binding pro-apoptotic Bax, inhibiting its mitochondrial localization, and attenuating Bax-mediated apoptosis activation
[2]. HN was also shown to act directly on Bax in isolated mitochondria suggesting that a cell surface receptor may not be required for its anti-apoptotic action
[2] though some studies suggest involvement of the cell surface receptor FPRL-1
[12],
[13]. A recent study has demonstrated that HN protects neurons by binding to a complex or complexes involving CNTFR/WSX-1/gp130
[13]. Moreover, neuronal protection by HN involves activation of tyrosine kinases and STAT-3 phosphorylation
[14], while the inhibition of tyrosine kinases or the use of dominant negative STAT3 prevented the anti-apoptotic action of HN. Furthermore, HN delays apoptosis in K562 cells by downregulation of p38 MAP kinase
[15] and prevents cell death in a constitutively activated Jun N-terminal kinase (JNK) cell line, suggesting that an important mechanism of cell protection could be via interfering with JNK activity
[16].
The interaction between HN and IGFBP-3 is especially interesting since IGFBP-3 and HN have opposing roles on cell survival, such that HN protects against while IGFBP-3 induces cell death
[17]. We previously demonstrated that HN physically binds with IGFBP-3 and that this interaction prevents the activation of caspases
[11]. More recently, we showed that IGFBP-3, independent of IGF-1, induces insulin resistance both at the liver and periphery through the hypothalamus as well as by direct action
[18],
[19]. Based upon the molecular interaction between HN and IGFBP-3 and the emerging link between AD and insulin resistance
[20], we hypothesized that HN, in addition to its neuroprotective roles, may serve as a centrally-acting regulator of glucose homeostasis. In a series of experiments, we examined the role of HN in glucose metabolism and its potential mechanism of action, including its interaction with IGFBP-3, by using HN and a variety of HN analogs. We also examined if there were changes in the levels of HN in circulation and in tissues with age.
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