Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, China.
J Biol Chem. 2021 Sep;297(3):101044. doi: 10.1016/j.jbc.2021.101044. Epub 2021 Aug 4.
Protein acetylation is a reversible posttranslational modification, which is regulated by lysine acetyltransferase (KAT) and lysine deacetyltransferase (KDAC). Although protein acetylation has been shown to regulate synaptic plasticity, this was mainly for histone protein acetylation. The function and regulation of nonhistone protein acetylation in synaptic plasticity and learning remain largely unknown. Calmodulin (CaM), a ubiquitous Ca sensor, plays critical roles in synaptic plasticity such as long-term potentiation (LTP). During LTP induction, activation of NMDA receptor triggers Ca influx, and the Ca binds with CaM and activates calcium/calmodulin-dependent protein kinase IIα (CaMKIIα). In our previous study, we demonstrated that acetylation of CaM was important for synaptic plasticity and fear learning in mice. However, the KAT responsible for CaM acetylation is currently unknown. Here, following an HEK293 cell-based screen of candidate KATs, steroid receptor coactivator 3 (SRC3) is identified as the most active KAT for CaM. We further demonstrate that SRC3 interacts with and acetylates CaM in a Ca and NMDA receptor-dependent manner. We also show that pharmacological inhibition or genetic downregulation of SRC3 impairs CaM acetylation, synaptic plasticity, and contextual fear learning in mice. Moreover, the effects of SRC3 inhibition on synaptic plasticity and fear learning could be rescued by 3KQ-CaM, a mutant form of CaM, which mimics acetylation. Together, these observations demonstrate that SRC3 acetylates CaM and regulates synaptic plasticity and learning in mice.
蛋白质乙酰化是一种可逆的翻译后修饰，受赖氨酸乙酰转移酶（KAT）和赖氨酸去乙酰化酶（KDAC）的调节。虽然已经证明蛋白质乙酰化可以调节突触可塑性，但这主要是针对组蛋白蛋白质乙酰化而言。非组蛋白蛋白质乙酰化在突触可塑性和学习中的功能和调节仍然知之甚少。钙调蛋白（CaM）是一种普遍存在的 Ca 传感器，在突触可塑性（如长时程增强（LTP））中发挥关键作用。在 LTP 诱导过程中，NMDA 受体的激活引发 Ca 内流，Ca 与 CaM 结合并激活钙/钙调蛋白依赖性蛋白激酶 IIα（CaMKIIα）。在我们之前的研究中，我们证明了 CaM 的乙酰化对于小鼠的突触可塑性和恐惧学习很重要。然而，目前尚不清楚负责 CaM 乙酰化的 KAT。在这里，我们通过基于 HEK293 细胞的候选 KAT 筛选，鉴定出类固醇受体共激活因子 3（SRC3）是 CaM 的最活跃 KAT。我们进一步证明，SRC3 以 Ca 和 NMDA 受体依赖的方式与 CaM 相互作用并乙酰化 CaM。我们还表明，药理学抑制或基因下调 SRC3 会损害 CaM 乙酰化、突触可塑性和小鼠的情景恐惧学习。此外，SRC3 抑制对突触可塑性和恐惧学习的影响可以通过 3KQ-CaM 挽救，3KQ-CaM 是一种模拟乙酰化的 CaM 突变体。综上所述，这些观察结果表明 SRC3 乙酰化 CaM 并调节小鼠的突触可塑性和学习。
