Molybdopterin biosynthesis pathway contributes to the regulation of SaeRS two-component system by ClpP in Staphylococcus aureus.
Molybdopterin biosynthesis pathway contributes to the regulation of SaeRS two-component system by ClpP in Staphylococcus aureus.
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DOI：
10.1080/21505594.2022.2065961
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发表时间：
2022-12
期刊：
影响因子：
5.2
通讯作者：
Liu, Qian
中科院分区：
文献类型：
--
作者：
Zhao, Na;Wang, Yanan;Liu, Junlan;Yang, Ziyu;Jian, Ying;Wang, Hua;Ahmed, Mahmoud;Li, Min;Bae, Taeok;Liu, Qian
在金黄色葡萄球菌中，SaeRS双组分系统对细菌的溶血活性和毒力是必不可少的。金黄色葡萄球菌纽曼株含有一种SAEs传感蛋白的变异体SAEs L18P。以前，我们证明，在纽曼菌株中，SAEs L18P被膜结合的蛋白酶FtsH降解。有趣的是，编码细胞质蛋白水解酶ClpP的ClpP基因敲除突变极大地降低了SAEs L18P的表达。在此，我们报道了在纽曼菌株中，ClpP对SAEs L18P表达的正向调节作用是由于它对FtsH的不稳定作用和对钼掺杂生物合成蛋白MOEA的降解。虽然ClpP对FtsH的转录没有影响，但在ClpP突变体中，FtsH的表达水平增加。这种不稳定作用似乎是间接的，因为在体外试验中，ClpXP不直接降解FtsH。通过转座子诱变，我们发现编码钼蝶呤生物合成蛋白A的MOEA基因抑制了金黄色葡萄球菌的溶血活性，同时抑制了SAES L18P的转录和表达。在蛋白分解实验中，ClpXP直接降解MOEA，证明MOEA是该酶的底物。在小鼠血流感染模型中，与WT株相比，MOEA突变体的毒力和存活率都有所降低。根据这些结果，我们得出结论，ClpP以FtsH和MOEA依赖的方式正向调控SAEs L18P的表达，MOEA的生理作用大于其在感染过程中对SAERS TCS的抑制作用。
In Staphylococcus aureus, the SaeRS two-component system is essential for the bacterium’s hemolytic activity and virulence. The Newman strain of S. aureus contains a variant of SaeS sensor kinase, SaeS L18P. Previously, we showed that, in the strain Newman, SaeS L18P is degraded by the membrane-bound protease FtsH. Intriguingly, the knockout mutation of clpP, encoding the cytoplasmic protease ClpP, greatly reduces the expression of SaeS L18P. Here, we report that, in the strain Newman, the positive regulatory role of ClpP on the SaeS L18P expression is due to its destabilizing effect on FtsH and degradation of MoeA, a molybdopterin biosynthesis protein. Although the transcription of ftsH was not affected by ClpP, the expression level of FtsH was increased in the clpP mutant. The destabilizing effect appears to be indirect because ClpXP did not directly degrade FtsH in an in vitro assay. Through transposon mutagenesis, we found out that the moeA gene, encoding the molybdopterin biosynthesis protein A, suppresses the hemolytic activity of S. aureus along with the transcription and expression of SaeS L18P. In a proteolysis assay, ClpXP directly degraded MoeA, demonstrating that MoeA is a substrate of the protease. In a murine bloodstream infection model, the moeA mutant displayed reduced virulence and lower survival compared with the WT strain. Based on these results, we concluded that ClpP positively controls the expression of SaeS L18P in an FtsH and MoeA-dependent manner, and the physiological role of MoeA outweighs its suppressive effect on the SaeRS TCS during infection.
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