The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2.
The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2.
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DOI：
10.1074/jbc.m110.123729
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发表时间：
2010-06-25
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影响因子：
--
通讯作者：
Zelcer N
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文献类型：
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作者：
Hong C;Duit S;Jalonen P;Out R;Scheer L;Sorrentino V;Boyadjian R;Rodenburg KW;Foley E;Korhonen L;Lindholm D;Nimpf J;van Berkel TJ;Tontonoz P;Zelcer N
我们之前已经鉴定出 E3 泛素连接酶诱导的低密度脂蛋白受体 (LDLR) 降解剂 (Idol) 作为 LDLR 水平的翻译后调节剂。 Idol 是肝脏 X 受体 (LXR) 调节的直接靶标，其表达对细胞甾醇状态有反应，独立于甾醇反应元件结合蛋白。在这里，我们证明 Idol 还针对两个密切相关的 LDLR 家族成员，即 VLDLR 和 ApoE 受体 2 (ApoER2)，这两种蛋白质与神经元发育和脂质代谢有关。 Idol 会触发细胞质尾部的 VLDLR 和 ApoER2 泛素化，导致其降解。我们进一步表明，内源性 VLDLR 的水平对细胞甾醇含量、Idol 表达和 LXR 途径的激活敏感。小鼠中 LXR 途径的药理学激活导致体内 Idol 表达增加和 Vldlr 水平降低。最后，我们在 LXR 和 Reelin 信号之间建立了意想不到的功能联系。我们证明 LXR 激活会导致 Reelin 与 VLDLR 的结合减少并减少 Dab1 磷酸化。 VLDLR 和 ApoER2 被鉴定为 Idol 靶标表明，除了脂质代谢之外，这种 LXR 诱导型 E3 连接酶在中枢神经系统中也具有潜在作用。
We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism.