Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production
Panfeng Tao, Shihao Wang, Seza Özen, Pui Y. Lee, Jiahui Zhang, Jun Wang, Huan Han, Zhao‐hui Yang, Ran Fang, Wanxia Li Tsai, Huanming Yang, Erdal Sağ, Rezan Topaloğlu, Ivona Aksentijevich, Xiaomin Yu, Qing Zhou
Abstract
OTULIN is a linear deubiquitinase that negatively regulates the nuclear factor κB (NF-κB) 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-κB 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.