Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130.
Humanin (HN) inhibits neuronal death induced by various Alzheimer's disease (AD)-related insults via an unknown receptor on cell membranes. Our earlier study indicated that the activation of STAT3 was essential for HN-induced neuroprotection, suggesting that the HN receptor may belong to the cytokine receptor family. In this study, a series of loss-of-function tests indicated that gp130, the common subunit of receptors belonging to the IL-6 receptor family, was essential for HN-induced neuroprotection. Overexpression of ciliary neurotrophic factor receptor alpha (CNTFR) and/or the IL-27 receptor subunit, WSX-1, but not that of any other tested gp130-related receptor subunit, up-regulated HN binding to neuronal cells, whereas siRNA-mediated knockdown of endogenous CNTFR and/or WSX-1 reduced it. These results suggest that both CNTFR and WSX-1 may be also involved in HN binding to cells. Consistent with these results, loss-of-functions of CNTFR or WSX-1 in neuronal cells nullified their responsiveness to HN-mediated protection. In vitro-reconstituted binding assays showed that HN, but not the other control peptide, induced the hetero-oligomerization of CNTFR, WSX-1, and gp130. Together, these results indicate that HN protects neurons by binding to a complex or complexes involving CNTFR/WSX-1/gp130.
Hashimoto
Yuichi
Y
Department of Pharmacology and Neuroscience, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.
Kurita
Megumi
M
Aiso
Sadakazu
S
Nishimoto
Ikuo
I
Matsuoka
Masaaki
M
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D018123:Receptors, Interleukin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism
D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; C112441:IL27RA protein, human; D047908:Intracellular Signaling Peptides and Proteins; D021122:Protein Subunits; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C427211:humanin; D050822:Cytokine Receptor gp130