14-3-3θ Phosphorylation at S232 reduces its interactome and regulates axonal trafficking.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
F Sanders Pair, Rudradip Pattanayak, James A Mobley, Kyoko Kojima, Mary Gannon, Roschongporn Ekkatine, William J Stone, Kasandra Scholz, Talene A Yacoubian
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引用次数: 0

Abstract

14-3-3 proteins impact protein-protein interactions (PPIs) that regulate neuronal functions. The 14-3-3θ isoform is protective in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) models. Human PD and DLB brains show increased 14-3-3θ phosphorylation at S232. To understand the impact of 14-3-3θ phosphorylation on brain PPIs, we performed affinity-purification mass spectrometry (AP-MS) using S232 phospho-mutant knock-in models. Proteins binding 14-3-3θ in Cre control cortical lysates were enriched in proteins involved in neuronal morphogenesis and microtubule dynamics. We found a dramatic decrease in proteins binding to 14-3-3θ in S232D mice compared to S232A mice. Axonal trafficking associated with these differentially binding proteins. Live imaging of acidic vesicles in axons revealed reduced net velocity in S232A and S232D neurons compared to Cre controls. In S232D neurons, this was due to a dramatic increase in vesicle pausing, while S232A neurons showed reduced segmental velocity, suggesting disrupted dynein motility. We conclude 14-3-3θ phosphorylation fine tunes axonal transport of acidic vesicles. Disruption of axonal transport with aberrant phosphorylation observed in PD and DLB could contribute to impaired clearance of aggregated proteins in these disorders.

14-3-3θ S232磷酸化减少其相互作用组并调节轴突运输。
14-3-3蛋白影响调节神经元功能的蛋白-蛋白相互作用(PPIs)。14-3-3θ亚型对帕金森病(PD)和路易体痴呆(DLB)模型具有保护作用。PD和DLB人大脑S232位点14-3-3θ磷酸化增加。为了了解14-3-3θ磷酸化对脑PPIs的影响,我们使用S232磷酸化突变敲入模型进行了亲和纯化质谱(AP-MS)。Cre对照皮质裂解物中结合14-3-3θ的蛋白富含参与神经元形态发生和微管动力学的蛋白。我们发现与S232A小鼠相比,S232D小鼠中结合14-3-3θ的蛋白质显著减少。轴突运输与这些差异结合蛋白有关。轴突酸性囊泡的实时成像显示,与Cre对照组相比,S232A和S232D神经元的净速度降低。在S232D神经元中,这是由于囊泡暂停的急剧增加,而S232A神经元显示节段速度降低,表明动力蛋白运动受到破坏。我们认为14-3-3θ磷酸化精细调节酸性囊泡轴突运输。在PD和DLB中观察到的轴突运输异常磷酸化的破坏可能导致这些疾病中聚集蛋白的清除受损。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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