Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.
András N SpaanAnna-Lena NeehusEmmanuel LaplantineFrederik StaelsMasato OgishiYoann SeeleuthnerFranck RapaportKeenan A LaceyErika Van NieuwenhoveMaya ChrabiehDavid HumMélanie MigaudAraksya IzmiryanLazaro LorenzoTatiana KochetkovDani A C HeesterbeekBart W BardoelAshley L DuMontA Kerry DobbsSolenne ChardonnetSøren HeisselTimour BaslanPeng ZhangJean-Laurent CasanovaDusan BogunovicHerman F WunderinkPieter-Jan A HaasHenrik MolinaGriet Van BuggenhoutStanislas LyonnetLuigi Daniele NotarangeloMikko R J SeppänenRobert WeilGisela SeminarioHéctor Gomez-TelloCarine WoutersMehrnaz MesdaghiMohammad ShahrooeiXavier BossuytErdal SağRezan TopaloğluSeher SenerHelen L LeavisMaarten M J van EijkLiliana BezrodnikLizbeth Blancas-GaliciaAlain HovnanianAude NassifBrigitte Bader-MeunierBénédicte NevenIsabelle MeytsRik SchrijversAnne PuelJacinta BustamanteIvona AksentijevichDaniel L KastnerVictor J TorresStephanie Humblet-BaronAdrian ListonLaurent AbelBertrand BoissonJean Laurent CasanovaPublished in: Science (New York, N.Y.) (2022)
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.
Keyphrases
- staphylococcus aureus
- escherichia coli
- nuclear factor
- endothelial cells
- methicillin resistant staphylococcus aureus
- end stage renal disease
- biofilm formation
- copy number
- single cell
- peripheral blood
- cell therapy
- chronic kidney disease
- toll like receptor
- induced pluripotent stem cells
- induced apoptosis
- prognostic factors
- newly diagnosed
- rheumatoid arthritis
- peritoneal dialysis
- oxidative stress
- extracellular matrix
- pluripotent stem cells
- pseudomonas aeruginosa
- small molecule
- genome wide
- signaling pathway
- cell death
- wound healing
- stem cells
- patient reported
- cell proliferation
- inflammatory response