Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production

Tao P., Wang S., ÖZEN S., Lee P. Y., Zhang J., Wang J., ...More

SCIENCE ADVANCES, vol.7, no.47, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 7 Issue: 47
  • Publication Date: 2021
  • Doi Number: 10.1126/sciadv.abi6794
  • Journal Name: SCIENCE ADVANCES
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, Compendex, EMBASE, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Hacettepe University Affiliated: Yes


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.