The histidine kinase NahK regulates pyocyanin production through the PQS system
The histidine kinase NahK regulates pyocyanin production through the PQS system
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DOI：
10.1128/jb.00276-23
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发表时间：
2023-08
影响因子：
3.2
通讯作者：
Alicia G. Mendoza;Danielle Guercio;Marina K. Smiley;Gaurav Sharma;Jason M. Withorn;Natalie V. Hudson-Smith;Chika Ndukwe;L. Dietrich;Elizabeth M. Boon
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文献类型：
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作者：
Alicia G. Mendoza;Danielle Guercio;Marina K. Smiley;Gaurav Sharma;Jason M. Withorn;Natalie V. Hudson-Smith;Chika Ndukwe;L. Dietrich;Elizabeth M. Boon
**摘要** 许多细菌组氨酸激酶在双组分系统中发挥作用，这些双组分系统又组合成更大的多激酶网络。NahK是GacS多激酶网络（MKN）中的激酶之一，该网络控制着机会致病菌铜绿假单胞菌的生物被膜调控。这个网络还与调控铜绿假单胞菌分泌的多种致病因子有关，这些致病因子会引发疾病。然而，每种激酶的具体作用尚不清楚。在本研究中，我们发现NahK是吩嗪类物质绿脓菌素（PYO）的一种新型调节因子。敲除nahK基因会导致PYO产量增加四倍，几乎完全是通过上调吩嗪操纵子2（phz2）实现的。我们确定这种上调是由于铜绿假单胞菌所有群体感应（QS）系统的调节异常所致，其中假单胞菌喹诺酮信号系统大幅上调，而酰基高丝氨酸内酯生成系统las的产量下降。此外，我们还观察到群体感应抑制蛋白的表达差异与这些变化一致。综合来看，这些数据有助于理解GacS MKN如何调节群体感应和毒力，并为群体感应的细胞密度非依赖性调节机制提供了思路。
**重要性** 铜绿假单胞菌是一种革兰氏阴性菌，形成生物被膜是其致病机制的一部分。铜绿假单胞菌感染与医院感染相关。随着多重耐药铜绿假单胞菌的流行率上升，了解其潜在的毒力分子机制至关重要。组氨酸激酶NahK是铜绿假单胞菌中与生物被膜形成和分散有关的几种激酶之一。先前的研究表明，一氧化氮传感器NosP通过抑制NahK触发生物被膜的分散。本文所展示的数据表明，NahK在铜绿假单胞菌的生存方式中还发挥着其他重要作用，包括调节群体感应等细菌通讯机制。这些影响在感染方面具有更广泛的意义，因为它们会影响毒素产生和毒力。铜绿假单胞菌是一种革兰氏阴性菌，形成生物被膜是其致病机制的一部分。铜绿假单胞菌感染与医院感染相关。随着多重耐药铜绿假单胞菌的流行率上升，了解其潜在的毒力分子机制至关重要。组氨酸激酶NahK是铜绿假单胞菌中与生物被膜形成和分散有关的几种激酶之一。先前的研究表明，一氧化氮传感器NosP通过抑制NahK触发生物被膜的分散。本文所展示的数据表明，NahK在铜绿假单胞菌的生存方式中还发挥着其他重要作用，包括调节群体感应等细菌通讯机制。这些影响在感染方面具有更广泛的意义，因为它们会影响毒素产生和毒力。
ABSTRACT Many bacterial histidine kinases work in two-component systems that combine into larger multi-kinase networks. NahK is one of the kinases in the GacS Multi-Kinase Network (MKN), which is the MKN that controls biofilm regulation in the opportunistic pathogen Pseudomonas aeruginosa. This network has also been associated with regulating many virulence factors P. aeruginosa secretes to cause disease. However, the individual role of each kinase is unknown. In this study, we identify NahK as a novel regulator of the phenazine pyocyanin (PYO). Deletion of nahK leads to a fourfold increase in PYO production, almost exclusively through upregulation of phenazine operon two (phz2). We determined that this upregulation is due to mis-regulation of all P. aeruginosa quorum-sensing (QS) systems, with a large upregulation of the Pseudomonas quinolone signal system and a decrease in production of the acyl-homoserine lactone-producing system, las. In addition, we see differences in expression of quorum-sensing inhibitor proteins that align with these changes. Together, these data contribute to understanding how the GacS MKN modulates QS and virulence and suggest a mechanism for cell density-independent regulation of quorum sensing. IMPORTANCE Pseudomonas aeruginosa is a Gram-negative bacterium that establishes biofilms as part of its pathogenicity. P. aeruginosa infections are associated with nosocomial infections. As the prevalence of multi-drug-resistant P. aeruginosa increases, it is essential to understand underlying virulence molecular mechanisms. Histidine kinase NahK is one of several kinases in P. aeruginosa implicated in biofilm formation and dispersal. Previous work has shown that the nitric oxide sensor, NosP, triggers biofilm dispersal by inhibiting NahK. The data presented here demonstrate that NahK plays additional important roles in the P. aeruginosa lifestyle, including regulating bacterial communication mechanisms such as quorum sensing. These effects have larger implications in infection as they affect toxin production and virulence. Pseudomonas aeruginosa is a Gram-negative bacterium that establishes biofilms as part of its pathogenicity. P. aeruginosa infections are associated with nosocomial infections. As the prevalence of multi-drug-resistant P. aeruginosa increases, it is essential to understand underlying virulence molecular mechanisms. Histidine kinase NahK is one of several kinases in P. aeruginosa implicated in biofilm formation and dispersal. Previous work has shown that the nitric oxide sensor, NosP, triggers biofilm dispersal by inhibiting NahK. The data presented here demonstrate that NahK plays additional important roles in the P. aeruginosa lifestyle, including regulating bacterial communication mechanisms such as quorum sensing. These effects have larger implications in infection as they affect toxin production and virulence.