PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Lucia Iannotta, Rachel Fasiczka, Giulia Favetta, Yibo Zhao, Elena Giusto, Elena Dall'Ara, Jianning Wei, Franz Y Ho, Claudia Ciriani, Susanna Cogo, Isabella Tessari, Ciro Iaccarino, Maxime Liberelle, Luigi Bubacco, Jean-Marc Taymans, Claudia Manzoni, Arjan Kortholt, Laura Civiero, Sabine Hilfiker, Michael L Lu, Elisa Greggio
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Abstract

P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinson's disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins. Here, to gain more insights into PAK6 physiological function, we performed protein-protein interaction arrays and identified a subgroup of PAK6 binders related to ciliogenesis. We confirmed that endogenous PAK6 localizes at both the centrosome and the cilium, and positively regulates ciliogenesis not only in tumor cells but also in neurons and astrocytes. Notably, PAK6 rescues ciliogenesis and centrosomal cohesion defects associated with the G2019S but not the R1441C LRRK2 PD mutation. Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.

PAK6能以突变特异性方式挽救LRRK2介导的致病性纤毛生成和中心体内聚缺陷。
P21活化激酶6(PAK6)是一种丝氨酸-苏氨酸激酶,在大脑中具有丰富的生理表达,并在一些人类肿瘤中过度表达。虽然 PAK6 在癌细胞中的作用已被广泛研究,但该激酶在脑细胞中的生理功能却鲜为人知。我们之前的研究发现了PAK6与帕金森病(PD)相关激酶LRRK2之间的联系,PAK6通过磷酸化14-3-3蛋白控制LRRK2的活性和亚细胞定位。在此,为了进一步了解PAK6的生理功能,我们进行了蛋白质-蛋白质相互作用阵列分析,发现了与纤毛生成相关的PAK6结合子群。我们证实,内源性 PAK6 定位于中心体和纤毛体,不仅在肿瘤细胞中,而且在神经元和星形胶质细胞中都对纤毛的生成起着积极的调节作用。值得注意的是,PAK6能挽救与G2019S而非R1441C LRRK2 PD突变相关的纤毛生成和中心体内聚缺陷。由于PAK6通过其GTPase/Roc-COR结构域与LRRK2结合,而R1441C突变位于Roc结构域,因此我们使用微尺度热泳和基于AlphaFold2的计算分析证明,影响Roc-COR结构的LRRK2 PD突变会大大降低PAK6的亲和力,这为PAK6对不同形式的突变LRRK2具有不同的保护作用提供了理论依据。总之,我们的研究揭示了 PAK6 在纤毛生成中的新作用,并指出 PAK6 是第一个具有 PD 突变特异性的 LRRK2 修饰符。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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