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., ...Daha Fazla

SCIENCE, cilt.376, sa.6599, ss.1285-1347, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 376 Sayı: 6599
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1126/science.abm6380
  • Dergi Adı: SCIENCE
  • Derginin Tarandığı İndeksler: 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
  • Sayfa Sayıları: ss.1285-1347
  • Hacettepe Üniversitesi Adresli: Evet

Özet

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.