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

Spaan, Andras; Neehus, Anna-Lena; Laplantine, Emmanuel; Staels, Frederik; Ogishi, Masato; Seeleuthner, Yoann; Rapaport, Franck; Lacey, Keenan; Van Nieuwenhove, Erika; Chrabieh, Maya; Hum, David; Migaud, Melanie; Izmiryan, Araksya; Lorenzo, Lazaro; Kochetkov, Tatiana; Heesterbeek, Dani; Bardoel, Bart; DuMont, Ashley; Dobbs, Kerry; Chardonnet, Solenne; Heissel, Soren; Baslan, Timour; Zhang, Peng; Yang, Rui; Bogunovic, Dusan; Wunderink, Herman; Haas, Pieter-Jan; Molina, Henrik; Van Buggenhout, Griet; Lyonnet, Stanislas; Notarangelo, Luigi; Seppanen, Mikko; Weil, Robert; Seminario, Gisela; Gomez-Tello, Hector; Wouters, Carine; Mesdaghi, Mehrnaz; Shahrooei, Mohammad; Bossuyt, Xavier; SAĞ, ERDAL; TOPALOĞLU, REZAN; ÖZEN, SEZA; Leavis, Helen; van Eijk, Maarten; Bezrodnik, Liliana; Galicia, Lizbeth; Hovnanian, Alain; Nassif, Aude; Bader-Meunier, Brigitte; Neven, Benedicte; Meyts, Isabelle; Schrijvers, Rik; Puel, Anne; Bustamante, Jacinta; Aksentijevich, Ivona; Kastner, Daniel; Torres, Victor; Humblet-Baron, Stephanie; Liston, Adrian; Abel, Laurent; Boisson, Bertrand; Casanova, Jean-Laurent

doi:10.1126/science.abm6380

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

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Spaan A. N., Neehus A., Laplantine E., Staels F., Ogishi M., Seeleuthner Y., ...More

SCIENCE, vol.376, no.6599, pp.1285-1347, 2022 (SCI-Expanded)

Publication Type: Article / Article
Volume: 376 Issue: 6599
Publication Date: 2022
Doi Number: 10.1126/science.abm6380
Journal Name: SCIENCE
Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, Agricultural & Environmental Science Database, Animal Behavior Abstracts, Applied Science & Technology Source, Aquatic Science & Fisheries Abstracts (ASFA), Artic & Antarctic Regions, ATLA Religion Database, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Communication Abstracts, Computer & Applied Sciences, EBSCO Education Source, EMBASE, Environment Index, Gender Studies Database, Geobase, Linguistic Bibliography, MEDLINE, Metadex, MLA - Modern Language Association Database, Pollution Abstracts, Psycinfo, Public Affairs Index, Veterinary Science Database, zbMATH, DIALNET, Civil Engineering Abstracts
Page Numbers: pp.1285-1347
Hacettepe University Affiliated: Yes

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 kappa B 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 alpha-toxin. Naturally elicited antibodies against alpha-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to alpha-toxin in nonleukocytic cells.