Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway
Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway
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DOI：
10.1042/0264-6021:3390453
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发表时间：
1999-04-15
影响因子：
4.1
通讯作者：
Wojcikiewicz, RJH
中科院分区：
文献类型：
--
作者：
Oberdorf, J;Webster, JM;Wojcikiewicz, RJH
已知某些磷酸肌醇酶-C-连接的细胞表面受体的激活导致肌醇1，4，5-三磷酸[Ins（1，4，5）P-3]受体的蛋白水解加速，并因此导致Ins（1，4，5）P-3受体下调。在目前的研究中，我们试图确定是否泛素/蛋白酶体途径参与这种适应性反应。所提供的数据表明：（i）磷酸肌醇酶-C-连接受体的激活导致一系列细胞类型中Ins（1，4，5）P-3-受体的泛素化（AR 4 - 2 J细胞、INS-1细胞和大鼠小脑颗粒细胞），（ii）由这些受体的激活诱导的Ins（1，4，5）P-3受体下调被蛋白酶体抑制剂阻断，（iii）所有已知的Ins（1，4，5）P-3受体（I、II和III型）是泛素化的底物，（iv）当Ins（1，4，5）P-3受体与膜结合时发生泛素化，（v）Ins（1，4，5）P-3受体泛素化和下调仅由持续升高Ins（1，4，5）P-3浓度的那些激动剂刺激，和（vi）细胞中的一部分Ins（1，4，5）P-3受体（与I型受体无关的那些）可以抵抗泛素化和降解。总之，这些数据表明，泛素/蛋白酶体途径介导的Ins（1，4，5）P-3-受体下调，并建议，泛素化的刺激结合的Ins（1，4，5）P-3的受体。
Activation of certain phosphoinositidase-C-linked cell-surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] receptors and, thus, lead to Ins(1,4,5)P-3-receptor down-regulation. In the current study we have sought to determine whether the ubiquitin/proteasome pathway is involved in this adaptive response. The data presented show (i) that activation of phosphoinositidase-C-linked receptors causes Ins(1,4,5)P-3-receptor ubiquitination in a range of cell types (AR4-2J cells, INS-1 cells and rat cerebellar granule cells), (ii) that the Ins(1,4,5)P-3-receptor down-regulation induced by activation of these receptors is blocked by proteasome inhibitors, (iii) that all known Ins(I,4,5)P-3 receptors (types I, II and III) are substrates for ubiquitination, (iv) that ubiquitination occurs while Ins(1,4,5)P-3 receptors are membrane-bound, (v) that Ins(1,4,5)P-3-receptor ubiquitination and down-regulation are stimulated only by those agonists that elevate Ins(1,4,5)P-3 concentration persistently, and (vi) that a portion of cellular Ins(1,4, 5)P-3 receptors (those that are not type-I-receptor-associated) can be resistant to ubiquitination and degradation. In total these data indicate that the ubiquitin/proteasome pathway mediates Ins(1,4,5)P-3-receptor down-regulation and suggest that ubiquitination is stimulated by the binding of Ins(1,4,5)P-3 to its receptor.