TY - JOUR
T1 - Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome
AU - Hanakawa, Yasushi
AU - Schechter, Norman M.
AU - Lin, Chenyan
AU - Garza, Luis
AU - Li, Hong
AU - Yamaguchi, Takayuki
AU - Fudaba, Yasuyuki
AU - Nishifuji, Koji
AU - Sugai, Motoyuki
AU - Amagai, Masayuki
AU - Stanley, John R.
PY - 2002
Y1 - 2002
N2 - Bullous impetigo due to Staphylococcus aureus is one of the most common bacterial infections of man, and its generalized form, staphylococcal scalded skin syndrome (SSSS), is a frequent manifestation of staphylococcal epidemics in neonatal nurseries. Both diseases are mediated by exfoliative toxins (ETs), which show exquisite pathologic specificity in blistering only the superficial epidermis. We show that these toxins act as serine proteases with extremely focused molecular specificity to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extracellular domains 3 and 4. Mutation of the predicted catalytically active serine to alanine completely inhibits cleavage. The mutated ETs bind specifically to Dsg1 by immunofluorescence colocalization and by coimmunoprecipitation. Thus, ETs, through specific recognition and proteolytic cleavage of one structurally critical peptide bond in an adhesion molecule, cause its dysfunction and allow S. aureus to spread under the stratum corneum, the main barrier of the skin, explaining how, although they circulate through the entire body in SSSS, they cause pathology only in the superficial epidermis.
AB - Bullous impetigo due to Staphylococcus aureus is one of the most common bacterial infections of man, and its generalized form, staphylococcal scalded skin syndrome (SSSS), is a frequent manifestation of staphylococcal epidemics in neonatal nurseries. Both diseases are mediated by exfoliative toxins (ETs), which show exquisite pathologic specificity in blistering only the superficial epidermis. We show that these toxins act as serine proteases with extremely focused molecular specificity to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extracellular domains 3 and 4. Mutation of the predicted catalytically active serine to alanine completely inhibits cleavage. The mutated ETs bind specifically to Dsg1 by immunofluorescence colocalization and by coimmunoprecipitation. Thus, ETs, through specific recognition and proteolytic cleavage of one structurally critical peptide bond in an adhesion molecule, cause its dysfunction and allow S. aureus to spread under the stratum corneum, the main barrier of the skin, explaining how, although they circulate through the entire body in SSSS, they cause pathology only in the superficial epidermis.
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U2 - 10.1172/JCI0215766
DO - 10.1172/JCI0215766
M3 - Article
C2 - 12093888
AN - SCOPUS:0036307873
SN - 0021-9738
VL - 110
SP - 53
EP - 60
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -