Proteasome-dependent and -independent mechanisms for FosB destabilization:: identification of FosB degron domains and implications for ΔFosB stability
Proteasome-dependent and -independent mechanisms for FosB destabilization:: identification of FosB degron domains and implications for ΔFosB stability
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DOI：
10.1111/j.1460-9568.2007.05575.x
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发表时间：
2007-05-01
影响因子：
3.4
通讯作者：
Nestler, Eric J.
中科院分区：
文献类型：
--
作者：
Carle, Tiffany L.;Ohnishi, Yoshinori N.;Nestler, Eric J.
当长期承受压力、滥用药物或其他慢性刺激时，转录因子 Delta FosB (Delta FosB) 以特定区域的方式在大脑中积累。一旦被诱导，Delta FosB 会在慢性刺激停止后在大脑中持续存在至少几周。 Delta FosB 持续表达的生化基础仍不清楚。在这里，我们发现 FosB C 末端（由于选择性剪接而在 Delta FosB 中缺失）包含两个降解决定子结构域。全长 FosB C 端截短突变体的脉冲追踪实验表明，去除其大部分 C 端降解决定子可将其半衰期延长至四倍，并防止其蛋白酶体介导的降解和泛素化，其特性与 Delta FosB 类似。此外，去除产生 Delta FosB 的第二个降解决定子结构域，可进一步稳定 FosB，类似于双重稳定，但以不依赖于蛋白酶体的方式。这些数据表明，选择性剪接专门从 FosB 中去除两个不稳定元件，以生成寿命更长的转录因子 Delta FosB，以响应大脑的慢性扰动。
The transcription factor Delta FosB (Delta FosB) accumulates in a region-specific manner in the brain during chronic exposure to stress, drugs of abuse or other chronic stimuli. Once induced, Delta FosB persists in the brain for at least several weeks following cessation of the chronic stimulus. The biochemical basis of the persistent expression of Delta FosB has remained unknown. Here, we show that the FosB C-terminus, absent in Delta FosB as a result of alternative splicing, contains two degron domains. Pulse-chase experiments of C-terminal truncation mutants of full-length FosB indicate that removal of its most C-terminal degron increases its half-life similar to fourfold, and prevents its proteasome-mediated degradation and ubiquitylation, properties similar to Delta FosB. In addition, removal of a second degron domain, which generates Delta FosB, further stabilizes FosB similar to twofold, but in a proteasome-independent manner. These data indicate that alternative splicing specifically removes two destabilizing elements from FosB in order to generate a longer-lived transcription factor, Delta FosB, in response to chronic perturbations to the brain.