Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production

Tao P., Wang S., ÖZEN S., Lee P. Y., Zhang J., Wang J., ...Daha Fazla

SCIENCE ADVANCES, cilt.7, sa.47, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 7 Sayı: 47
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1126/sciadv.abi6794
  • Dergi Adı: SCIENCE ADVANCES
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, Compendex, EMBASE, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Hacettepe Üniversitesi Adresli: Evet

Özet

OTULIN is a linear deubiquitinase that negatively regulates the nuclear factor kappa B (NF-kappa B) signaling pathway. Patients with OTULIN deficiency, termed as otulipenia or OTULIN-related autoinflammatory syndrome, present with early onset severe systemic inflammation due to increased NF-kappa B activation. We aimed to investigate additional disease mechanisms of OTULIN deficiency. Our study found a remarkable activation of type I interferon (IFN-I) signaling in whole blood, peripheral blood mononuclear cells, monocytes, and serum from patients with OTULIN deficiency. We observed similar immunologic findings in OTULIN-deficient cell lines generated by CRISPR. Mechanistically, we identified proteasome subunits as substrates of OTULIN deubiquitinase activity and demonstrated proteasome dysregulation in OTULIN-deficient cells as the cause of IFN-I activation. These results reveal an important role of linear ubiquitination in the regulation of proteasome function and suggest a link in the pathogenesis of proteasome-associated autoinflammatory syndromes and OTULIN deficiency.