The Staphylococcus aureus secretome - TI Pharma

Mapping the pathways to staphylococcal pathogenesis by comparative secretomics
General introduction and scope of this review
The Gram-positive bacterium Staphylococcus aureus is a frequent component of the human
microbial flora that can turn into a dangerous pathogen. As such, this organism is capable of
infecting almost every tissue and organ system in the human body. It does so by exporting a
variety of virulence factors to the cell surface and extracellular milieu of the human host. As
in all living organisms (Wickner and Schekman, 2005), S. aureus contains several protein
transport pathways, of which the general secretory (Sec) pathway is the most well known and
best described. Proteins that need to be transported to an extracytoplasmic location contain, in
general, an N-terminal signal peptide that is needed to target the newly synthesized protein
from the ribosome to the translocation machinery in the cytoplasmic membrane. Next, the
protein is threaded through the Sec translocon in an unfolded state. During this translocation
step, or shortly thereafter, the signal peptide is removed by a so-called signal peptidase. Upon
complete membrane translocation, the protein has to fold into its correct conformation and
will then be retained in an extracytoplasmic compartment of the cell, or secreted into the
extracellular milieu. In the case of Gram-positive cocci, such as S. aureus (Figure 1), we
distinguish three extracytoplasmic subcellular compartments: the membrane, the membranecell
wall interface and the cell wall. Since surface-exposed and secreted proteins of S. aureus
play pivotal roles in the colonization and subversion of the human host, it is of major
importance to obtain a clear understanding of the protein transport pathways that are active in
this organism (Lee and Schneewind, 2001). Knowledge about the protein sorting mechanism
has become all the more relevant with the upcoming of staphylococcal resistance against lastdefence
antibiotics, such as vancomycin. The scope of this review is to provide a state-of-theart
roadmap of staphylococcal secretomes, which include both protein transport pathways and
the extracytoplasmic proteins of these organisms. The focus is on S. aureus, but comparisons
with Staphylococcus epidermidis and the best characterized Gram-positive bacterium Bacillus
subtilis are included where appropriate. Importantly, the present review aims to integrate the
results of genomic and proteomic studies on S. aureus secretomes, representing the first
documented “comparative secretomics” study. Specifically, this review deals with known and
predicted exported virulence factors, pathways for protein transport, signals for subcellular
protein sorting or secretion, and the exoproteomes of different S. aureus isolates as defined by
two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry
(Figures 2 and 3). The exoproteome is defined by all S. aureus proteins that can be identified
in the extracellular milieu of this organism and thus includes proteins actively secreted by
living cells and the remains of dead cells. For a clear appreciation of the present review, it is
important to bear in mind that the proteins exported from the cytoplasm could be directly
involved in staphylococcal virulence, whereas the respective protein export systems represent
the “pathways to pathogenesis”.
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