The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels
The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels
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DOI：
10.1038/nn.2712
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发表时间：
2011-02-01
影响因子：
25
通讯作者：
Zamponi, Gerald W.
中科院分区：
文献类型：
--
作者：
Altier, Christophe;Garcia-Caballero, Agustin;Zamponi, Gerald W.
众所周知，辅助 Cav β 亚基调节质膜中的钙通道密度，但发生这种情况的细胞机制仍不清楚。我们发现 Cav β 亚基通过阻止通道进入内质网相关蛋白降解 (ERAD) 复合物来增加 Cav1.2 通道的膜表达。如果没有 Cav beta，Cav1.2 通道会被 RFP2 泛素连接酶强力泛素化，并与 ERAD 复合蛋白 derlin-1 和 p97 相互作用，最终将通道靶向蛋白酶体进行降解。在用蛋白酶体抑制剂 MG132 处理后，Cav 无β通道被从降解中拯救出来，并被运输到质膜上。 Cav beta 的共表达干扰了通道的泛素化和 ERAD 复合物的靶向，从而促进内质网的输出并促进细胞表面的表达。因此，Cav beta 调节钙通道复合物的泛素化和稳定性。
It is well established that the auxiliary Cav beta subunit regulates calcium channel density in the plasma membrane, but the cellular mechanism by which this occurs has remained unclear. We found that the Cav beta subunit increased membrane expression of Cav1.2 channels by preventing the entry of the channels into the endoplasmic reticulum-associated protein degradation (ERAD) complex. Without Cav beta, Cav1.2 channels underwent robust ubiquitination by the RFP2 ubiquitin ligase and interacted with the ERAD complex proteins derlin-1 and p97, culminating in targeting of the channels to the proteasome for degradation. On treatment with the proteasomal inhibitor MG132, Cav beta-free channels were rescued from degradation and trafficked to the plasma membrane. The coexpression of Cav beta interfered with ubiquitination and targeting of the channel to the ERAD complex, thereby facilitating export from the endoplasmic reticulum and promoting expression on the cell surface. Thus, Cav beta regulates the ubiquitination and stability of the calcium channel complex.