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Vol. 20, Issue 12, 2864-2873, June 15, 2009

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Humanin Inhibits Neuronal Cell Death by Interacting with a Cytokine Receptor Complex or Complexes Involving CNTF Receptor /WSX-1/gp130

Yuichi Hashimoto^*, Megumi Kurita^*, Sadakazu Aiso, Ikuo Nishimoto^,, and Masaaki Matsuoka^*

*Department of Pharmacology and Neuroscience, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan; and Departments of Anatomy, and Pharmacology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan

Submitted February 27, 2009; Revised March 30, 2009; Accepted April 15, 2009
Monitoring Editor: Donald D. Newmeyer

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 (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.

Deceased October 17, 2003.

Address correspondence to: Masaaki Matsuoka (sakimatu{at}tokyo-med.ac.jp)

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