Gene regulation in Streptococcus pneumoniae - RePub - Erasmus ...

histidine kinase is the sensor protein that resides in the cell membrane. Upon sensing and
binding of its ligand (e.g., sugars or peptides), the HK is activated and autophosphorylation of
a conserved histidine residue occurs. Usually, HK proteins are found as homodimers and
phosphorylation of the histidine residue on the first HK catalyzes phosphorylation of the
histidine residue on the second HK of the dimer (14). The second component is a cytosolic
protein called the response regulator (RR), which is a DNA-binding protein. The phosphoryl
group of the HK is transferred to an aspartate residue on the RR, after which the RR
undergoes a conformation change and becomes activated. The activated RR then acts as a
transcriptional regulator, repressing or activating gene expression.
Introduction
Sequence analysis of the pneumococcal genome has revealed the presence of 13
TCSs plus one so-called orphan response regulator (RitR) (46, 60). Knock-out mutants of
these genes were used to investigate their role in virulence of different serogroups in mice
(30, 61). Following these two large screening studies, more detailed studies have led to
further insight into the importance of pneumococcal TCSs in pathogenesis (for a complete
overview see 46).
The most studied TCS in S. pneumoniae is the ComDE system (TCS12), which is part
of the competence machinery (24). Natural competence is the state in which a bacterium is
able to take up DNA from its environment. Sequestered DNA can be inserted into the
chromosome, and novel genetic properties and pathogenic features can be acquired. The
histidine kinase ComD senses competence stimulating peptide (CSP), a small peptide of
which the precursor is produced by comC and is transported and cleaved to its mature state by
ComAB. When CSP accumulates to a critical concentration outside the cell, ComD will be
phosphorylated, and transfer of the phosphoryl group will activate the RR ComE, which in
turn activates the other components of the competence machinery. The transcriptional
regulator ComX is also activated, which subsequently activates many other genes involved in
DNA uptake and processing, bacteriocin production, and stress response (32, 49). The
ComDE TCS was demonstrated to be important for virulence, more specifically ComD was
shown to be involved in pneumonia and bacteremia in serotype 2 strain D39 (3), serotype 3
strain 0100993 (31) and serotype 4 strain TIGR4 (20). Using microarray-based transcriptional
profiling, over 200 CSP-responsive genes were identified (12, 49). These induced or
repressed genes included several known virulence factors such as autolysin lytA, a stress
response protein htrA, and the choline binding protein cbpD.
TCS04 was demonstrated to be involved in virulence during murine pneumonia (61),
and later the involvement was shown to be strain-dependent (37). Transcriptome analysis of
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