Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation.
Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation.
复制标题
DOI：
10.1038/nchembio.770
复制
发表时间：
2012-01-22
影响因子：
14.8
通讯作者：
Hsieh-Wilson, Linda C.
中科院分区：
文献类型：
--
作者：
Rexach, Jessica E.;Clark, Peter M.;Mason, Daniel E.;Neve, Rachael L.;Peters, Eric C.;Hsieh-Wilson, Linda C.
转录因子CREB是许多神经元过程的关键调节因子，包括大脑发育、昼夜节律和长期记忆。对CREB的研究主要集中在其磷酸化上，尽管大脑中CREB功能的多样性表明还有其他形式的调节。在这里，我们扩展了用于量化糖基化化学计量学的化学酶策略，以表征CREB糖基化在神经元中的功能作用。我们发现，CREB在神经元活性的响应中动态地受到o- glcnac修饰，糖基化通过损害CREB与共激活子CRTC/TORC的关联来抑制CREB依赖的转录。阻断CREB糖基化可改变细胞功能和行为可塑性，增强轴突和树突生长和长期记忆巩固。我们的发现证明了o -糖基化在记忆形成中的新作用，并提供了糖基化如何促进关键神经元功能的机制理解。此外，我们确定了一个以前未知的调节活动依赖基因表达、神经发育和记忆的机制。
The transcription factor CREB is a key regulator of many neuronal processes, including brain development, circadian rhythm, and long-term memory. Studies of CREB have focused on its phosphorylation, although the diversity of CREB functions in the brain suggests additional forms of regulation. Here we expand on a chemoenzymatic strategy for quantifying glycosylation stoichiometries to characterize the functional roles of CREB glycosylation in neurons. We show that CREB is dynamically O-GlcNAc-modified in response to neuronal activity and glycosylation represses CREB-dependent transcription by impairing its association with the co-activator CRTC/TORC. Blocking glycosylation of CREB altered cellular function and behavioral plasticity, enhancing both axonal and dendritic growth and long-term memory consolidation. Our findings demonstrate a new role for O-glycosylation in memory formation and provide a mechanistic understanding of how glycosylation contributes to critical neuronal functions. Moreover, we identify a previously unknown mechanism for the regulation of activity-dependent gene expression, neural development, and memory.
登录
查看更多内容
影响因子：
3
作者：
Francisco, Herb;Kollins, Katherine;Varghis, Neal;Vocadlo, David;Vosseller, Keith;Gallo, Gianluca
通讯作者：
Gallo, Gianluca
影响因子：
4.8
作者：
Lu, Q;Hutchins, AE;Kwok, RPS
通讯作者：
Kwok, RPS
影响因子：
25
作者：
Kida, S;Josselyn, SA;Silva, AJ
通讯作者：
Silva, AJ
影响因子：
64.5
作者：
BOURTCHULADZE, R;FRENGUELLI, B;SILVA, AJ
通讯作者：
SILVA, AJ
影响因子：
56.9
作者：
Gambetta, Maria Cristina;Oktaba, Katarzyna;Mueller, Juerg
通讯作者：
Mueller, Juerg