FMRP-PKA 活性负反馈调节脑学习记忆回路中 RNA 结合依赖性纤维颤动。
FMRP-PKA Activity Negative Feedback Regulates RNA Binding-Dependent Fibrillation in Brain Learning and Memory Circuitry.
机构信息
Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37235, USA; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37235, USA; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37235, USA; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37235, USA.
出版信息
Cell Rep. 2020 Oct 13;33(2):108266. doi: 10.1016/j.celrep.2020.108266.
Fragile X mental retardation protein (FMRP) promotes cyclic AMP (cAMP) signaling. Using an in vivo protein kinase A activity sensor (PKA-SPARK), we find that Drosophila FMRP (dFMRP) and human FMRP (hFMRP) enhance PKA activity in a central brain learning and memory center. Increasing neuronal PKA activity suppresses FMRP in Kenyon cells, demonstrating an FMRP-PKA negative feedback loop. A patient-derived R140Q FMRP point mutation mislocalizes PKA-SPARK activity, whereas deletion of the RNA-binding arginine-glycine-glycine (RGG) box (hFMRP-ΔRGG) produces fibrillar PKA-SPARK assemblies colocalizing with ribonucleoprotein (RNP) and aggregation (thioflavin T) markers, demonstrating fibrillar partitioning of cytosolic protein aggregates. hFMRP-ΔRGG reduces dFMRP levels, indicating RGG-independent regulation. Short-term hFMRP-ΔRGG induction produces activated PKA-SPARK puncta, whereas long induction drives fibrillar assembly. Elevated temperature disassociates hFMRP-ΔRGG aggregates and blocks activated PKA-SPARK localization. These results suggest that FMRP regulates compartmentalized signaling via complex assembly, directing PKA activity localization, with FMRP RGG box RNA binding restricting separation via low-complexity interactions.
脆性 X 智力低下蛋白 (FMRP) 促进环磷酸腺苷 (cAMP) 信号转导。我们使用一种体内蛋白激酶 A 活性传感器 (PKA-SPARK)，发现果蝇 FMRP (dFMRP) 和人类 FMRP (hFMRP) 在大脑学习和记忆中心增强 PKA 活性。增加神经元 PKA 活性可抑制 Kenyon 细胞中的 FMRP，表明存在 FMRP-PKA 负反馈回路。一个源自患者的 R140Q FMRP 点突变导致 PKA-SPARK 活性的定位错误，而 RNA 结合精氨酸-甘氨酸-甘氨酸 (RGG) 盒 (hFMRP-ΔRGG) 的缺失则产生与核糖核蛋白 (RNP) 和聚集 (硫代黄素 T) 标记物共定位的 PKA-SPARK 纤维状组装体，表明细胞质蛋白聚集体的纤维状分隔。hFMRP-ΔRGG 降低了 dFMRP 的水平，表明存在 RGG 非依赖性调节。hFMRP-ΔRGG 的短期诱导产生激活的 PKA-SPARK 点状结构，而长期诱导则导致纤维状组装。升高的温度会使 hFMRP-ΔRGG 聚集体解聚并阻止激活的 PKA-SPARK 定位。这些结果表明，FMRP 通过复杂组装调节区室化信号，指导 PKA 活性定位，FMRP RGG 盒 RNA 结合通过低复杂度相互作用限制分离。
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