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

SUBMITTER: Spaan AN

PROVIDER: S-EPMC9233084 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Spaan András N AN Neehus Anna-Lena AL Laplantine Emmanuel E Staels Frederik F Ogishi Masato M Seeleuthner Yoann Y Rapaport Franck F Lacey Keenan A KA Van Nieuwenhove Erika E Chrabieh Maya M Hum David D Migaud Mélanie M Izmiryan Araksya A Lorenzo Lazaro L Kochetkov Tatiana T Heesterbeek Dani A C DAC Bardoel Bart W BW DuMont Ashley L AL Dobbs Kerry K Chardonnet Solenne S Heissel Søren S Baslan Timour T Zhang Peng P Yang Rui R Bogunovic Dusan D Wunderink Herman F HF Haas Pieter-Jan A PA Molina Henrik H Van Buggenhout Griet G Lyonnet Stanislas S Notarangelo Luigi D LD Seppänen Mikko R J MRJ Weil Robert R Seminario Gisela G Gomez-Tello Héctor H Wouters Carine C Mesdaghi Mehrnaz M Shahrooei Mohammad M Bossuyt Xavier X Sag Erdal E Topaloglu Rezan R Ozen Seza S Leavis Helen L HL van Eijk Maarten M J MMJ Bezrodnik Liliana L Blancas Galicia Lizbeth L Hovnanian Alain A Nassif Aude A Bader-Meunier Brigitte B Neven Bénédicte B Meyts Isabelle I Schrijvers Rik R Puel Anne A Bustamante Jacinta J Aksentijevich Ivona I Kastner Daniel L DL Torres Victor J VJ Humblet-Baron Stéphanie S Liston Adrian A Abel Laurent L Boisson Bertrand B Casanova Jean-Laurent JL

Science (New York, N.Y.) 20220617 6599

The molecular basis of interindividual clinical variability upon infection with <i>Staphylococcus aureus</i> 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 <i>S. aureus</i> infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of ...[more]

PMID: 35587511

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Project description:Human immunodeficiency virus (HIV) has a very narrow host range. HIV type 1 (HIV-1) does not infect Old World monkeys, such as the rhesus monkey (Rh). Rh TRIM5α was identified as a factor that confers resistance, intrinsic immunity, to HIV-1 infection. Unfortunately, human TRIM5α is almost powerless to restrict HIV-1. However, human TRIM5α potently restricts N-tropic murine leukemia viruses (MLV) but not B-tropic MLV, indicating that human TRIM5α represents the restriction factor previously designated as Ref1. African green monkey TRIM5α represents another restriction factor previously designated as Lv1, which restricts both HIV-1 and simian immunodeficiency virus isolated from macaque (SIVmac) infection. TRIM5 is a member of the tripartite motif family containing RING, B-box2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase, and TRIM5α is thought to degrade viral core via ubiquitin-proteasome-dependent and -independent pathways. The alpha isoform of TRIM5 has an additional C-terminal PRYSPRY domain, which is a determinant of species-specific retrovirus restriction by TRIM5α. On the other hand, the target regions of viral capsid protein (CA) are scattered on the surface of core. A single amino acid difference in the surface-exposed loop between α-helices 6 and 7 (L6/7) of HIV type 2 (HIV-2) CA affects viral sensitivity to human TRIM5α and was also shown to be associated with viral load in West African HIV-2 patients, indicating that human TRIM5α is a critical modulator of HIV-2 replication in vivo. Interestingly, L6/7 of CA corresponds to the MLV determinant of sensitivity to mouse factor Fv1, which potently restricts N-tropic MLV. In addition, human genetic polymorphisms also affect antiviral activity of human TRIM5α. Recently, human TRIM5α was shown to activate signaling pathways that lead to activation of NF-κB and AP-1 by interacting with TAK1 complex. TRIM5α is thus involved in control of viral infection in multiple ways.

Dataset Information

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

Publications

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

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