Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production.
Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production.
复制标题
OTULIN 对蛋白酶体亚基的去泛素化可调节 I 型 IFN 的产生
DOI：
10.1126/sciadv.abi6794
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发表时间：
2021-11-19
期刊：
影响因子：
13.6
通讯作者：
Zhou Q
中科院分区：
文献类型：
--
作者：
Tao P;Wang S;Ozen S;Lee PY;Zhang J;Wang J;Han H;Yang Z;Fang R;Tsai WL;Yang H;Sag E;Topaloglu R;Aksentijevich I;Yu X;Zhou Q
OTULIN对蛋白酶体亚基的去泛素化调节I型IFN的产生。OTULIN是一种线性去泛素化酶，可负调节核因子κB（NF-κB）信号通路。患有OTULIN缺乏症的患者，称为OTULIN或OTULIN相关的自身炎症综合征，由于NF-κB活化增加而表现出早期发作的严重全身性炎症。我们的目的是研究OTULIN缺乏症的其他疾病机制。我们的研究发现，在全血、外周血单核细胞、单核细胞和来自OTULIN缺乏症患者的血清中，I型干扰素（IFN-I）信号传导显著活化。我们在CRISPR产生的OTULIN缺陷细胞系中观察到类似的免疫学发现。从机制上讲，我们确定了蛋白酶体亚基作为OTULIN去泛素化酶活性的底物，并证明了OTULIN缺陷细胞中蛋白酶体失调是IFN-1活化的原因。这些结果揭示了线性泛素化在调节蛋白酶体功能中的重要作用，并表明蛋白酶体相关自身炎症综合征和OTULIN缺乏症的发病机制中存在联系。
Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production. 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.