Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Neurobiol Learn Mem. 2019 Jan;157:1-11. doi: 10.1016/j.nlm.2018.11.012. Epub 2018 Nov 17.
Numerous studies have supported a critical role for the ubiquitin-proteasome system (UPS) in the memory consolidation and reconsolidation processes. The protein targets and functional role of ubiquitin-proteasome activity can vary widely across cellular compartments, however, it is unknown how UPS activity changes within the nuclear, cytoplasmic, and synaptic regions in response to learning or memory retrieval. Additionally, while previous studies have focused on degradation-specific protein polyubiquitination, it is unknown how learning alters other polyubiquitin tags that are not targeted by the proteasome. Using cellular fractionation protocols in combination with linkage-specific polyubiquitin antibodies, we examined subcellular changes in ubiquitin-proteasome activity in the amygdala during memory consolidation and reconsolidation. Following memory acquisition, overall protein ubiquitination and proteasome activity simultaneously increased in the nucleus and decreased in the synaptic and cytoplasmic regions. The nuclear increases were associated with upregulation of degradation-specific (K48) and degradation-independent (K63, M1) polyubiquitin tags, suggesting multiple functions for ubiquitin signaling within this region. Interestingly, retrieval induced a very different pattern of ubiquitin-proteasome activity in the amygdala, consisting of increases in overall protein ubiquitination and proteasome activity and K48-, K63-, and M1-polyubiquitin tags in the synaptic, but not nuclear or cytoplasmic regions. Collectively, learning and memory retrieval dynamically and differentially alter degradation-dependent and degradation-independent ubiquitin-proteasome activity across different cellular compartments, suggesting that the UPS may serve unique functions during memory consolidation and reconsolidation.
大量研究支持泛素-蛋白酶体系统（UPS）在记忆巩固和再巩固过程中的关键作用。然而，蛋白质靶标和泛素-蛋白酶体活性的功能作用在细胞区室之间差异很大，目前尚不清楚 UPS 活性如何在核、细胞质和突触区室中响应学习或记忆检索而变化。此外，虽然先前的研究集中在降解特异性蛋白多泛素化上，但尚不清楚学习如何改变其他未被蛋白酶体靶向的多泛素标签。我们使用细胞分离方案结合连接特异性多泛素抗体，研究了记忆巩固和再巩固期间杏仁核中 UPS 活性的亚细胞变化。在记忆获得后，核内的总蛋白泛素化和蛋白酶体活性同时增加，而突触和细胞质区域的活性降低。核内的增加与降解特异性（K48）和非降解特异性（K63、M1）多泛素标签的上调有关，表明泛素信号在该区域具有多种功能。有趣的是，检索在杏仁核中诱导了一种非常不同的泛素-蛋白酶体活性模式，包括总蛋白泛素化和蛋白酶体活性以及 K48、K63 和 M1 多泛素标签的增加，但突触而不是核或细胞质区域。总之，学习和记忆检索在不同的细胞区室中动态和差异地改变了依赖降解和不依赖降解的泛素-蛋白酶体活性，表明 UPS 在记忆巩固和再巩固过程中可能具有独特的功能。
