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OTULIN limits cell death and inflammation by deubiquitinating LUBAC.
Heger, Klaus; Wickliffe, Katherine E; Ndoja, Ada; Zhang, Juan; Murthy, Aditya; Dugger, Debra L; Maltzman, Allie; de Sousa E Melo, Felipe; Hung, Jeffrey; Zeng, Yi; Verschueren, Erik; Kirkpatrick, Donald S; Vucic, Domagoj; Lee, Wyne P; Roose-Girma, Merone; Newman, Robert J; Warming, Søren; Hsiao, Yi-Chun; Komuves, László G; Webster, Joshua D; Newton, Kim; Dixit, Vishva M.
Afiliación
  • Heger K; Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  • Wickliffe KE; Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  • Ndoja A; Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  • Zhang J; Department of Translational Immunology, Genentech, South San Francisco, CA, USA.
  • Murthy A; Department of Cancer Immunology, Genentech, South San Francisco, CA, USA.
  • Dugger DL; Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  • Maltzman A; Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  • de Sousa E Melo F; Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
  • Hung J; Department of Pathology, Genentech, South San Francisco, CA, USA.
  • Zeng Y; Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  • Verschueren E; Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  • Kirkpatrick DS; Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  • Vucic D; Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA.
  • Lee WP; Department of Translational Immunology, Genentech, South San Francisco, CA, USA.
  • Roose-Girma M; Department of Molecular Biology, Genentech, South San Francisco, CA, USA.
  • Newman RJ; Department of Molecular Biology, Genentech, South San Francisco, CA, USA.
  • Warming S; Department of Molecular Biology, Genentech, South San Francisco, CA, USA.
  • Hsiao YC; Department of Antibody Engineering, Genentech, South San Francisco, CA, USA.
  • Komuves LG; Department of Pathology, Genentech, South San Francisco, CA, USA.
  • Webster JD; Department of Pathology, Genentech, South San Francisco, CA, USA.
  • Newton K; Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. knewton@gene.com.
  • Dixit VM; Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. dixit@gene.com.
Nature ; 559(7712): 120-124, 2018 07.
Article en En | MEDLINE | ID: mdl-29950720
OTULIN (OTU deubiquitinase with linear linkage specificity) removes linear polyubiquitin from proteins that have been modified by LUBAC (linear ubiquitin chain assembly complex) and is critical for preventing auto-inflammatory disease1,2 and embryonic lethality during mouse development3. Here we show that OTULIN promotes rather than counteracts LUBAC activity by preventing its auto-ubiquitination with linear polyubiquitin. Thus, knock-in mice that express catalytically inactive OTULIN, either constitutively or selectively in endothelial cells, resembled LUBAC-deficient mice4 and died midgestation as a result of cell death mediated by TNFR1 (tumour necrosis factor receptor 1) and the kinase activity of RIPK1 (receptor-interacting protein kinase 1). Inactivation of OTULIN in adult mice also caused pro-inflammatory cell death. Accordingly, embryonic lethality and adult auto-inflammation were prevented by the combined loss of cell death mediators: caspase 8 for apoptosis and RIPK3 for necroptosis. Unexpectedly, OTULIN mutant mice that lacked caspase 8 and RIPK3 died in the perinatal period, exhibiting enhanced production of type I interferon that was dependent on RIPK1. Collectively, our results indicate that OTULIN and LUBAC function in a linear pathway, and highlight a previously unrecognized interaction between linear ubiquitination, regulators of cell death, and induction of type I interferon.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endopeptidasas / Muerte Celular / Ubiquitina / Ubiquitinación / Enzimas Desubicuitinizantes / Inflamación Límite: Animals Idioma: En Revista: Nature Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endopeptidasas / Muerte Celular / Ubiquitina / Ubiquitinación / Enzimas Desubicuitinizantes / Inflamación Límite: Animals Idioma: En Revista: Nature Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido