Abstract
In the Gram-positive pathogen Staphylococcus aureus, the membrane-bound ATP-dependent metalloprotease FtsH plays a critical role in resistance to various stressors. However, the molecular mechanism of the FtsH functions is not known. Here, we identified core FtsH target proteins in S. aureus. In the strains Newman and USA300, the abundance of 33 proteins were altered in both strains, of which 11 were identified as core FtsH substrate protein candidates. In the strain Newman and some other S. aureus strains, the sensor histidine kinase SaeS has an L18P (T53C in saeS) substitution, which transformed the protein into an FtsH substrate. Due to the increase of SaeS L18P in the ftsH mutant, Eap, a sae-regulon protein, was also increased in abundance, causing the Newman-specific cell-aggregation phenotype. Regardless of the strain background, however, the ftsH mutants showed lower virulence and survival in a murine infection model. Our study illustrates the elasticity of the bacterial regulatory network, which can be rewired by a single substitution mutation.
Highlights
In the Gram-positive pathogen Staphylococcus aureus, the membrane-bound ATP-dependent metalloprotease FtsH plays a critical role in resistance to various stressors
To study the roles of FtsH in two different strain backgrounds, we deleted the ftsH gene in S. aureus strain Newman and USA300
By combining mass spectrometry (MS)-based proteomics and RNA-seq, we identified 11 potential FtsH core substrate proteins in S. aureus (Fig. 2 and Table 1)
Summary
In the Gram-positive pathogen Staphylococcus aureus, the membrane-bound ATP-dependent metalloprotease FtsH plays a critical role in resistance to various stressors. ATP-dependent proteolysis machines (ClpXP, ClpAP, ClpCP, HslUV, Lon, and FtsH) play critical roles in protein quality control by eliminating misassembled or misfolded proteins and proteins no longer needed[1] Of those proteases, FtsH is a Zn metalloprotease tethered to the cell membrane via the two transmembrane segments located at N-terminus[2]. Exchange chromatography/SDS-PAGE and two-dimensional gel electrophoresis to find 10 cytoplasmic and membrane proteins whose abundance is significantly increased in the ftsH-deletion mutant of Corynebacterium glutamicum[12]. This method requires rather extensive sample preparations and does not exclude the possibility that some of the proteins might be affected by FtsH indirectly. The underlying molecular mechanisms of those phenotypes have not yet been understood
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