Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:4.2.3.23 (
GAS
)
957
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Group A Streptococcus (Streptococcus pyogenes or
GAS
) causes pharyngitis, severe invasive infections, and the post-infectious syndromes of glomerulonephritis and rheumatic fever.
GAS
can be internalized and killed by epithelial cells in vitro, a process that may contribute to local innate defense against pharyngeal infection. Secretion of the pore-forming toxin streptolysin O (SLO) by
GAS
has been reported to stimulate targeted autophagy (xenophagy) upon internalization of the bacteria by epithelial cells. Whereas this process was associated with killing of
GAS
in HeLa cells, studies in human keratinocytes found SLO production enhanced intracellular survival. To reconcile these conflicting observations, we now report in-depth investigation of xenophagy in response to
GAS
infection of human oropharyngeal keratinocytes, the predominant cell type of the pharyngeal epithelium. We found that SLO expression was associated with prolonged intracellular survival; unexpectedly, expression of the co-toxin NADase was required for this effect. Enhanced intracellular survival was lost upon deletion of NADase or inactivation of its enzymatic activity. Shortly after internalization of
GAS
by keratinocytes, SLO-mediated damage to the bacteria-containing vacuole resulted in exposure to the cytosol, ubiquitination of
GAS
and/or associated vacuolar membrane remnants, and engulfment of
GAS
in LC3-positive vacuoles. We also found that production of streptolysin S could mediate targeting of
GAS
to autophagosomes in the absence of SLO, a process accompanied by
galectin 8
binding to damaged
GAS
-containing endosomes. Maturation of
GAS
-containing autophagosome-like vacuoles to degradative autolysosomes was prevented by SLO pore-formation and by SLO-mediated translocation of enzymatically active NADase into the keratinocyte cytosol. We conclude that SLO stimulates xenophagy in pharyngeal keratinocytes, but the coordinated action of SLO and NADase prevent maturation of
GAS
-containing autophagosomes, thereby prolonging
GAS
intracellular survival. This novel activity of NADase to block autophagic killing of
GAS
in pharyngeal cells may contribute to pharyngitis treatment failure, relapse, and chronic carriage.
...
PMID:Streptolysin O and its co-toxin NAD-glycohydrolase protect group A Streptococcus from Xenophagic killing. 2376 25
