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Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin

2022; American Association for the Advancement of Science; Volume: 376; Issue: 6599 Linguagem: Inglês

10.1126/science.abm6380

1095-9203

András N. Spaan, Anna‐Lena Neehus, Emmanuel Laplantine, Frederik Staels, Masato Ogishi, Yoann Seeleuthner, Franck Rapaport, Keenan A. Lacey, Erika Van Nieuwenhove, Maya Chrabieh, David Hum, Mélanie Migaud, Araksya Izmiryan, Lazaro Lorenzo, Tatiana Kochetkov, Dani A. C. Heesterbeek, Bart W. Bardoel, Ashley Dumont, Kerry Dobbs, Solenne Chardonnet, Søren Heissel, Timour Baslan, Peng Zhang, Rui Yang, Dusan Bogunovic, Herman F. Wunderink, Pieter-Jan Haas, Henrik Molina, Griet Van Buggenhout, Stanislas Lyonnet, Luigi D. Notarangelo, Mikko Seppänen, Robert Weil, Gisela Seminario, Héctor Gomez-Tello, Carine Wouters, Mehrnaz Mesdaghi, Mohammad Shahrooei, Xavier Bossuyt, Erdal Sağ, Rezan Topaloğlu, Seza Özen, Helen L. Leavis, Maarten M. J. van Eijk, Liliana Bezrodnik, Lizbeth Blancas‐Galicia, Alain Hovnanian, Aude Nassif, Brigitte Bader‐Meunier, Bénédicte Neven, Isabelle Meyts, Rik Schrijvers, Anne Puel, Jacinta Bustamante, Ivona Aksentijevich, Daniel L. Kastner, Victor J. Torres, Stéphanie Humblet‐Baron, Adrian Liston, Laurent Abel, Bertrand Boisson, Jean‐Laurent Casanova,

Antimicrobial Resistance in Staphylococcus

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.