Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin
Publication date
2022-06-17
Authors
Spaan, András N
Neehus, Anna Lena
Laplantine, Emmanuel
Staels, Frederik
Ogishi, Masato
Seeleuthner, Yoann
Rapaport, Franck
Lacey, Keenan A.
van Nieuwenhove, Erika
Chrabieh, Maya
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Supervisors
Document Type
Article
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taverne
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 kB 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 a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.
Keywords
Bacterial Toxins/immunology, Cri-du-Chat Syndrome/genetics, Endopeptidases/genetics, Haploinsufficiency/genetics, Hemolysin Proteins/immunology, Host-Pathogen Interactions/genetics, Humans, Immunity, Cellular/genetics, Necrosis, Staphylococcal Infections/genetics, Staphylococcus aureus, Taverne, General, Journal Article
Citation
Spaan, A N, Neehus, A L, Laplantine, E, Staels, F, Ogishi, M, Seeleuthner, Y, Rapaport, F, Lacey, K A, Van Nieuwenhove, E, Chrabieh, M, Hum, D, Migaud, M, Izmiryan, A, Lorenzo, L, Kochetkov, T, Heesterbeek, D A C, Bardoel, B W, DuMont, A L, Dobbs, K, Chardonnet, S, Heissel, S, Baslan, T, Zhang, P, Yang, R, Bogunovic, D, Wunderink, H F, Haas, P J A, Molina, H, Van Buggenhout, G, Lyonnet, S, Notarangelo, L D, Seppänen, M R J, Weil, R, Seminario, G, Gomez-Tello, H, Wouters, C, Mesdaghi, M, Shahrooei, M, Bossuyt, X, Sag, E, Topaloglu, R, Ozen, S, Leavis, H L, van Eijk, M M J, Bezrodnik, L, Galicia, L B, Hovnanian, A, Nassif, A, Bader-Meunier, B, Neven, B, Meyts, I, Schrijvers, R, Puel, A, Bustamante, J, Aksentijevich, I, Kastner, D L, Torres, V J, Humblet-Baron, S, Liston, A, Abel, L, Boisson, B & Casanova, J L 2022, 'Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin', Science, vol. 376, no. 6599, eabm6380. https://doi.org/10.1126/science.abm6380