Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.
Science
; 376(6599): eabm6380, 2022 06 17.
Article
em En
| MEDLINE
| ID: mdl-35587511
ABSTRACT
The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.
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Base de dados:
MEDLINE
Assunto principal:
Endopeptidases
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Infecções Estafilocócicas
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Staphylococcus aureus
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Toxinas Bacterianas
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Síndrome de Cri-du-Chat
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Haploinsuficiência
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Proteínas Hemolisinas
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article