Department of Cellular and Physiological Sciences, Life Sciences Institute and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
J Cell Sci. 2023 Apr 1;136(7). doi: 10.1242/jcs.260629. Epub 2023 Apr 5.
Activity-induced changes in protein palmitoylation can regulate the plasticity of synaptic connections, critically impacting learning and memory. Palmitoylation is a reversible post-translational modification regulated by both palmitoyl-acyl transferases that mediate palmitoylation and palmitoyl thioesterases that depalmitoylate proteins. However, it is not clear how fluctuations in synaptic activity can mediate the dynamic palmitoylation of neuronal proteins. Using primary hippocampal cultures, we demonstrate that synaptic activity does not impact the transcription of palmitoylating and depalmitoylating enzymes, changes in thioesterase activity, or post-translational modification of the depalmitoylating enzymes of the ABHD17 family and APT2 (also known as LYPLA2). In contrast, synaptic activity does mediate post-translational modification of the palmitoylating enzymes ZDHHC2, ZDHHC5 and ZDHHC9 (but not ZDHHC8) to influence protein-protein interactions, enzyme stability and enzyme function. Post-translational modifications of the ZDHHC enzymes were also observed in the hippocampus following fear conditioning. Taken together, our findings demonstrate that signaling events activated by synaptic activity largely impact activity of the ZDHHC family of palmitoyl-acyl transferases with less influence on the activity of palmitoyl thioesterases.
活动诱导的蛋白质棕榈酰化变化可以调节突触连接的可塑性，对学习和记忆有重要影响。棕榈酰化是一种由介导棕榈酰化的棕榈酰酰基转移酶和去棕榈酰化蛋白的棕榈酰硫酯酶调节的可逆翻译后修饰。然而，目前尚不清楚突触活动的波动如何调节神经元蛋白的动态棕榈酰化。我们使用原代海马培养物证明，突触活动不会影响棕榈酰化和去棕榈酰化酶的转录、硫酯酶活性的变化，也不会改变 ABHD17 家族和 APT2（也称为 LYPLA2）去棕榈酰化酶的翻译后修饰。相比之下，突触活动确实介导棕榈酰化酶 ZDHHC2、ZDHHC5 和 ZDHHC9（但不是 ZDHHC8）的翻译后修饰，从而影响蛋白质-蛋白质相互作用、酶稳定性和酶功能。在恐惧条件反射后，海马体中也观察到 ZDHHC 酶的翻译后修饰。总之，我们的研究结果表明，由突触活动激活的信号事件主要影响 ZDHHC 家族的棕榈酰酰基转移酶的活性，对棕榈酰硫酯酶的活性影响较小。
