UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP.
UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP.
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DOI：
10.1016/j.bcp.2015.08.084
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发表时间：
2015-10-15
影响因子：
5.8
通讯作者：
De Biasi M
中科院分区：
文献类型：
--
作者：
Teng Y;Rezvani K;De Biasi M
含有α3亚基的神经元烟碱乙酰胆碱受体（nAChRs）在正常神经节传递中具有重要作用，而其参与尼古丁成瘾和吸烟相关疾病的机制是近年来才出现的。关于含α3的nAChRs的成熟和运输的信息量有限。我们先前表明，UBXN 2A是一种p97衔接蛋白，可促进含α3的nAChRs的成熟和运输。对UBXN 2A作用机制的进一步研究表明，该蛋白与CHIP（Hsc 70相互作用蛋白的羧基末端）相互作用，CHIP的泛素E3连接酶活性调节几种疾病相关蛋白的降解。我们发现，CHIP显示对α3 nAChR亚基的E3连接酶活性，并有助于其泛素化和随后的降解。UBXN 2A干扰CHIP介导的α3泛素化，并保护烟碱受体亚基免受内质网相关降解（ERAD）。UBXN 2A还与VCP/p97和HSC 70/HSP 70蛋白在复合物中发生交联，其中α3可能被CHIP靶向。总的来说，我们确定CHIP作为α3的E3连接酶，UBXN 2A作为可以有效调节CHIP客户底物稳定性的蛋白质。
Neuronal nicotinic acetylcholine receptors (nAChRs) containing the α3 subunit are known for their prominent role in normal ganglionic transmission while their involvement in the mechanisms underlying nicotine addiction and smoking-related disease has been emerging only in recent years. The amount of information available on the maturation and trafficking of α3-containing nAChRs is limited. We previously showed that UBXN2A is a p97 adaptor protein that facilitates the maturation and trafficking of α3-containing nAChRs. Further investigation of the mechanisms of UBXN2A actions revealed that the protein interacts with CHIP (carboxyl terminus of Hsc70 interacting protein), whose ubiquitin E3 ligase activity regulates the degradation of several disease-related proteins. We show that CHIP displays E3 ligase activity toward the α3 nAChR subunit and contributes to its ubiquitination and subsequent degradation. UBXN2A interferes with CHIP-mediated ubiquitination of α3 and protects the nicotinic receptor subunit from endoplasmic reticulum associated degradation (ERAD). UBXN2A also cross-talks with VCP/p97 and HSC70/HSP70 proteins in a complex where α3 is likely to be targeted by CHIP. Overall, we identify CHIP as an E3 ligase for α3 and UBXN2A as a protein that may efficiently regulate the stability of CHIP’s client substrates.
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