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

• Published in: Science (American Association for the Advancement of Science) Vol. 376; no. 6599; p. eabm6380
• Main 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, Hum, David, Migaud, Mélanie, Izmiryan, Araksya, Lorenzo, Lazaro, Kochetkov, Tatiana, Heesterbeek, Dani A C, Bardoel, Bart W, DuMont, Ashley L, Dobbs, Kerry, Chardonnet, Solenne, Heissel, Søren, Baslan, Timour, Zhang, Peng, Yang, Rui, Bogunovic, Dusan, Wunderink, Herman F, Haas, Pieter-Jan A, Molina, Henrik, Van Buggenhout, Griet, Lyonnet, Stanislas, Notarangelo, Luigi D, Seppänen, Mikko R J, Weil, Robert, Seminario, Gisela, Gomez-Tello, Héctor, Wouters, Carine, Mesdaghi, Mehrnaz, Shahrooei, Mohammad, Bossuyt, Xavier, Sag, Erdal, Topaloglu, Rezan, Ozen, Seza, Leavis, Helen L, van Eijk, Maarten M J, Bezrodnik, Liliana, Blancas Galicia, Lizbeth, Hovnanian, Alain, Nassif, Aude, Bader-Meunier, Brigitte, Neven, Bénédicte, Meyts, Isabelle, Schrijvers, Rik, Puel, Anne, Bustamante, Jacinta, Aksentijevich, Ivona, Kastner, Daniel L, Torres, Victor J, Humblet-Baron, Stéphanie, Liston, Adrian, Abel, Laurent, Boisson, Bertrand, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 17.06.2022; American Association for the Advancement of Science (AAAS)
• Subjects: Accumulation; Age; Antibodies; Bacterial Toxins - immunology; Caveolin; Caveolin-1; Cell surface; Chromosome 5; Chromosome aberrations; Chromosome deletion; Cri-du-Chat Syndrome - genetics; Cri-du-Chat Syndrome - immunology; Crosstalk; Cytotoxicity; Deletion; Disease; Endopeptidases - genetics; Enrichment; Fibroblasts; Genomes; Haploinsufficiency; Haploinsufficiency - genetics; Haploinsufficiency - immunology; Hemolysin Proteins - immunology; Heredity; Heterozygotes; Homogeneity; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Immunity; Immunity, Cellular - genetics; Infectious diseases; Leukocytes; Life Sciences; Lung diseases; Lungs; Lysine; Metalloproteinase; Mutation; Necrosis; Neutralizing; NF-κB protein; Patients; Phenotypes; Receptors; Signaling; Skin diseases; Staphylococcal Infections - genetics; Staphylococcal Infections - immunology; Staphylococcal Infections - pathology; Staphylococcus aureus; Staphylococcus infections; Toxicity; Toxins; Tumor necrosis factor; Tumor necrosis factor-TNF; Variability; Virulence; Virulence factors
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abm6380

The molecular basis of interindividual clinical variability upon infection with 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 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.