Journal
SCIENCE ADVANCES
Volume 7, Issue 47, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abi6794
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Funding
- National Key R&D Program of China [2018YFC1004903]
- National Natural Science Foundation of China [31771548, 81971528]
- Zhejiang Provincial Natural Science Foundation of China [LR19H100001]
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OTULIN deficiency leads to activation of NF-κB and IFN-I signaling pathways, caused by dysregulated proteasomes due to the deubiquitinase activity of OTULIN. This suggests a crucial role of linear ubiquitination in regulating proteasome function and its link to autoinflammatory syndromes associated with proteasome dysfunction.
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.
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