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

András Spaan , Anna-Lena Neehus (1) , Emmanuel Laplantine (2) , Frederik Staels , Masato Ogishi , Yoann Seeleuthner (1) , Franck Rapaport , Keenan Lacey , Erika van Nieuwenhove , Maya Chrabieh (1) , David Hum , Mélanie Migaud (1) , Araksya Izmiryan (1) , Lazaro Lorenzo (1) , Tatiana Kochetkov , Dani Heesterbeek , Bart Bardoel , Ashley Dumont , Kerry Dobbs , Solenne Chardonnet (3, 4) , Søren Heissel , Timour Baslan , Peng Zhang , Rui Yang , Dusan Bogunovic , Herman Wunderink , Pieter-Jan Haas , Henrik Molina , Griet van Buggenhout , Stanislas Lyonnet (1) , Luigi Notarangelo , Mikko Seppänen , Robert Weil , Gisela Seminario , Héctor Gomez-Tello , Carine Wouters , Mehrnaz Mesdaghi , Mohammad Shahrooei , Xavier Bossuyt , Erdal Sag , Rezan Topaloglu , Seza Ozen , Helen Leavis , Maarten van Eijk , Liliana Bezrodnik , Lizbeth Blancas Galicia , Alain Hovnanian (1) , Aude Nassif , Brigitte Bader-Meunier (1) , Bénédicte Neven (1) , Isabelle Meyts , Rik Schrijvers , Anne Puel (1) , Jacinta Bustamante (1) , Ivona Aksentijevich , Daniel Kastner , Victor Torres , Stéphanie Humblet-Baron , Adrian Liston , Laurent Abel (1) , Bertrand Boisson (1) , Jean-Laurent Casanova (1)

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 GenCellDis (U944 / UMR7212) - Génomes, biologie cellulaire et thérapeutiques
3 PASS - Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé
4 PASS-P3S - Plateforme Post-génomique de la Pitié-Salpêtrière

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.

Domains: Life Sciences [q-bio]

András Spaan, Anna-Lena Neehus, Emmanuel Laplantine, Frederik Staels, Masato Ogishi, et al.. Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin. Science, 2022, 376 (6599), ⟨10.1126/science.abm6380⟩. ⟨hal-03810222⟩