Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin Journal Article
| Authors: | 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.; Blanas Galicia, L.; 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. |
| Article Title: | Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin |
| 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. Copyright © 2022 The Authors, some rights reserved. |
| Keywords: | adolescent; adult; controlled study; human tissue; gene mutation; human cell; major clinical study; genetics; chromosome; gene expression; embryo; protein binding; cohort analysis; genome-wide association study; immunoglobulin enhancer binding protein; cytotoxicity; cellular immunity; fibroblast; proteinase; immunity; staphylococcus aureus; staphylococcus infection; staphylococcal infections; tumor; immune deficiency; immune response gene; chromosome deletion; polyubiquitin; chromosome 5p; penetrance; endopeptidases; autosomal dominant inheritance; disease; neutralizing antibody; virulence; receptor cross-talk; haploinsufficiency; adam10 endopeptidase; bacterial toxins; virulence factor; hemolysin proteins; purifying selection; caveolin 1; bacterial toxin; humans; human; article; staphylococcus alpha toxin; deubiquitinase; whole exome sequencing; gene set enrichment analysis; hemolysin; ubiquitin carboxyl terminal hydrolase cyld; staphylococcal alpha-toxin; otulin gene |
| Journal Title: | Science |
| Volume: | 376 |
| Issue: | 6599 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2022-06-17 |
| Start Page: | eabm6380 |
| Language: | English |
| DOI: | 10.1126/science.abm6380 |
| PUBMED: | 35587511 |
| PROVIDER: | scopus |
| PMCID: | PMC9233084 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
