Humanin Inhibits Neuronal Cell Death by Interacting with a Cytokine Receptor Complex or Complexes Involving CNTF Receptor α/WSX-1/gp130
Humanin Inhibits Neuronal Cell Death by Interacting with a Cytokine Receptor Complex or Complexes Involving CNTF Receptor α/WSX-1/gp130
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DOI：
10.1091/mbc.e09-02-0168
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发表时间：
2009-06-15
影响因子：
3.3
通讯作者：
Matsuoka, Masaaki
中科院分区：
文献类型：
--
作者：
Hashimoto, Yuichi;Kurita, Megumi;Matsuoka, Masaaki
人(HN)通过细胞膜上的一种未知受体抑制阿尔茨海默病(AD)相关的各种损伤引起的神经元死亡。我们早期的研究表明，STAT3的激活在HN诱导的神经保护中是必不可少的，提示HN受体可能属于细胞因子受体家族。在这项研究中，一系列功能丧失测试表明，gp130，属于IL-6受体家族的受体的共同亚单位，在HN诱导的神经保护中是必不可少的。过度表达睫状神经营养因子受体α(CNTFR)和/或IL-27受体亚基WSX-1，但不表达其他gp130相关受体亚基，可上调HN与神经细胞的结合，而siRNA介导的内源性CNTFR和/或WSX-1抑制HN与神经细胞的结合。这些结果表明，CNTFR和WSX-1可能都参与了HN与细胞的结合。与这些结果一致的是，神经细胞中CNTFR或WSX-1功能的丧失使其对HN介导的保护的反应性丧失。体外重组结合分析表明，HN诱导了CNTFR、WSX-1和gp130的异源寡聚，而不是另一个对照多肽。综上所述，这些结果表明HN通过与一个或多个涉及CNTFR/WSX-1/gp130的复合体结合来保护神经元。
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.