Abstract
A two-component system GtrS-GltR is required for glucose transport activity in P. aeruginosa and plays a key role during P. aeruginosa-host interactions. However, the mechanism of action of GtrS-GltR has not been definitively established. Here, we show that gltB, which encodes a periplasmic glucose binding protein, is essential for the glucose-induced activation of GtrS-GltR in P. aeruginosa. We determined that GltB is capable of binding to membrane regulatory proteins including GtrS, the sensor kinase of the GtrS-GltR TCS. We observed that alanine substitution of glucose-binding residues abolishes the ability of GltB to promote the activation of GtrS-GltR. Importantly, like the gtrS deletion mutant, gltB deletion mutant showed attenuated virulence in both Drosophila melanogaster and mouse models of infection. In addition, using CHIP-seq experiments, we showed that the promoter of gltB is the major in vivo target of GltR. Collectively, these data suggest that periplasmic binding protein GltB and GtrS-GltR TCS form a complex regulatory circuit that regulates the virulence of P. aeruginosa in response to glucose.
Highlights
Accepted: 18 February 2021Glucose is an essential nutrient for the human body, serving as a primary fuel for energy production [1]
It has been proposed that, in P. aeruginosa, when glucose passes the outer membrane through the OprB porin and reaches the periplasm, it can be transported by an ATP binding cassette (ABC) transport system (i.e., ABCGltBFGK, designated as ABCGtsABCD ) to the cytoplasm, or it can be oxidized in the periplasm by glucose dehydrogenase (Gcd) and gluconate dehydrogenase (Gad) to gluconate and 2-ketogluconate (2-KG) [20,21,22,23,24] (Figure 1A)
These results suggest that GtrS-GltR is essential for glucose utilization in P. aeruginosa strain when Gcd is absent, which support the no13 of 28 tion that in aerobically grown Pseudomonas species extracellular glucose can be catabolized by either the phosphorylative pathway or the oxidative pathway (Figure 1A)
Summary
Glucose is an essential nutrient for the human body, serving as a primary fuel for energy production [1]. Gluconate and 2-KG are subsequently transported to the cytoplasm via transporters GntP and KguT, respectively [22,25] (Figure 1A) Both the phosphorylative pathway, which converts glucose to Published: 21 February 2021. 2-KG and 6-phosphogluconate (6PG), two metabolic intermediates of glucose utilization pathways, can bind to ligand-binding domain of GtrS, leading to increase GtrS autophosphorylation and GltR phosphorylation activity [26]. GtrS plays a key role during P. aeruginosa-host interactions and is required for optimal colonization and dissemination in a mouse model of infection [28]. Intrigued by these findings, in this study, we decided to investigate the mechanism of action of GtrS-GltR TCS in P. aeruginosa PAO1
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