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American Association for the Advancement of Science, Science, 6599(376), 2022

DOI: 10.1126/science.abm6380



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

Journal article published in 2022 by András N. Spaan ORCID, Anna-Lena Neehus ORCID, Emmanuel Laplantine ORCID, Frederik Staels ORCID, Masato Ogishi ORCID, Yoann Seeleuthner, Franck Rapaport ORCID, Keenan A. Lacey ORCID, Erika Van Nieuwenhove ORCID, Maya Chrabieh, David Hum ORCID, Mélanie Migaud ORCID, Araksya Izmiryan ORCID, Lazaro Lorenzo ORCID, Tatiana Kochetkov and other authors.
This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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The molecular basis of interindividual clinical variability upon infection withStaphylococcus aureusis 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 byS. aureusinfection. 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.