A kinase-independent function of PAK is crucial for pathogen-mediated actin remodelling.
A kinase-independent function of PAK is crucial for pathogen-mediated actin remodelling.
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DOI：
10.1371/journal.ppat.1009902
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发表时间：
2021-08
期刊：
影响因子：
6.7
通讯作者：
Koronakis V
中科院分区：
文献类型：
--
作者：
Davidson A;Tyler J;Hume P;Singh V;Koronakis V
p21激活激酶（PAK）家族调节多种细胞过程，包括肌动蛋白细胞骨架重塑。许多细菌病原体篡夺宿主调节肌动蛋白重组的信号通路以促进感染。沙门氏菌和致病性大肠杆菌分别驱动肌动蛋白依赖的强制摄取和亲密附着。我们证明，病原体驱动的这两种不同的肌动蛋白结构的产生依赖于PAK的招募和激活。我们发现，PAK激酶结构域是这个肌动蛋白重塑，而不是需要GTP酶结合CRIB和中央聚脯氨酸丰富的区域。PAK与鸟嘌呤核苷酸交换因子β-PIX相互作用并抑制它，防止它对细胞骨架重组产生负面影响。PAK的这种激酶非依赖性功能可能被其他改变宿主细胞骨架信号传导的病原体所取代，这有助于我们更好地了解PAK在正常和患病真核细胞中的功能。许多细菌病原体通过重塑宿主细胞肌动蛋白细胞骨架来驱动感染，并且众所周知p21活化激酶（PAK）参与调节肌动蛋白动力学。沙门氏菌和EPEC产生非常不同的肌动蛋白结构，以促进侵入或附着到宿主细胞上。在这里，我们表明，这两种细菌劫持相同的PAK信号通路来实现这一目标。PAK的关键作用不依赖于其激酶活性，而是依赖于其与宿主鸟嘌呤核苷酸交换因子β-PIX相互作用的能力。PAK结合否定了β-PIX对允许侵入或附着的细菌驱动的肌动蛋白重塑的抑制作用。这是PAK的一种新的激酶非依赖性功能，可能被靶向宿主肌动蛋白细胞骨架信号传导的许多其他细菌和病毒病原体所使用。
The p21-activated kinase (PAK) family regulate a multitude of cellular processes, including actin cytoskeleton remodelling. Numerous bacterial pathogens usurp host signalling pathways that regulate actin reorganisation in order to promote Infection. Salmonella and pathogenic Escherichia coli drive actin-dependent forced uptake and intimate attachment respectively. We demonstrate that the pathogen-driven generation of both these distinct actin structures relies on the recruitment and activation of PAK. We show that the PAK kinase domain is dispensable for this actin remodelling, which instead requires the GTPase-binding CRIB and the central poly-proline rich region. PAK interacts with and inhibits the guanine nucleotide exchange factor β-PIX, preventing it from exerting a negative effect on cytoskeleton reorganisation. This kinase-independent function of PAK may be usurped by other pathogens that modify host cytoskeleton signalling and helps us better understand how PAK functions in normal and diseased eukaryotic cells. Many bacterial pathogens drive infection by remodelling the host cell actin cytoskeleton, and p21 activated kinases (PAK’s) are well known to be involved in modulating actin dynamics. Salmonella and EPEC generate very different actin structures in order to promote either invasion into or attachment onto host cells. Here we show that both bacteria hi-jack the same PAK signalling pathway to achieve this. PAK’s crucial role is independent of its kinase activity, and instead relies on its ability to interact the host guanine nucleotide exchange factor β-PIX. PAK binding negates the inhibitory effect β-PIX has on the bacterial driven-actin remodelling that permits either invasion or attachment. This is a novel kinase-independent function for PAK that is likely used by many other bacterial and viral pathogens that target host actin cytoskeleton signalling.
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