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    Home > Active Ingredient News > Immunology News > Science Advances Zhejiang University Qing Zhou/Xiamin Yu discovered a new regulatory mechanism for type I interferon production

    Science Advances Zhejiang University Qing Zhou/Xiamin Yu discovered a new regulatory mechanism for type I interferon production

    • Last Update: 2021-12-06
    • Source: Internet
    • Author: User
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    iNatureOTULIN is a linear deubiquitinating enzyme that negatively regulates the nuclear factor kappa B (NF-κB) signaling pathway
    .

    Patients with OTULIN deficiency, called otulipenia or OTULIN-related autoinflammatory syndrome, develop early-onset severe systemic inflammation due to increased NF-κB activation
    .

    The molecular pathogenesis of otulipenia is poorly understood
    .

    On November 19, 2021, Zhou Qing and Yu Xiaomin of Zhejiang University jointly published a research paper entitled "Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production" in Science Advances.
    The study found that the whole blood, Type I interferon (IFN-I) signals in peripheral blood mononuclear cells, monocytes and serum are significantly activated
    .

    The study observed similar immunological findings in CRISPR-generated OTULIN-deficient cell lines
    .

    In terms of mechanism, this study identified the proteasome subunit as a substrate of OTULIN deubiquitinating enzyme activity, and proved that the proteasome dysregulation in OTULIN-deficient cells is the cause of IFN-I activation
    .

    These results reveal the important role of linear ubiquitination in the regulation of proteasome function and indicate that there is a link between the pathogenesis of proteasome-related autoinflammatory syndrome and OTULIN deficiency
    .

    OTULIN [Ovarian tumor (OTU) deubiquitinating enzyme with linear junction specificity] is a methionine 1 (M1) linked deubiquitinating enzyme that can interact with LUBAC (linear ubiquitin chain assembly complex) to Remove the linear ubiquitin chain generated by LUBAC
    .

    Binding with LUBAC's catalytic subunit heme iron oxide response element binding protein 2 (IRP2) ubiquitin ligase-1 (HOIL-1) interacting protein (HOIP) to recruit OTULIN to the tumor necrosis factor receptor (TNFR) complex It also inhibits the nuclear factor κB (NF-κB) pathway
    .

     OTULIN also removes linear ubiquitin chains from other substrates, including NF-κB essential modulators (NEMO), receptor-interacting protein kinase 1 (RIPK1) and A20 to attenuate NF-κB signaling
    .

    The loss of HOIP-OTULIN interaction will reduce the ability of OTULIN to limit LUBAC-induced NF-κB activation
    .

    Due to pro-inflammatory cell death mediated by TNFR1 and RIPK1 kinase activity, knockout mice expressing catalytically inactive OTULIN died in the second trimester
    .

    Phosphorylation of OTULIN can regulate RIPK1 ubiquitination and promote necroptosis
    .

    In humans, biallelic loss of function (LoF) mutations in OTULIN can cause otulipenia, also known as OTULIN-associated autoinflammatory syndrome (ORAS), which is a form of fever, neutrophil dermatitis, panniculitis , Auto-inflammatory diseases/arthritis characterized by arthralgia, lymphadenopathy, hepatosplenomegaly, gastrointestinal inflammation and developmental delay
    .

    This potentially fatal disease is rare, as only 7 patients have been reported in the literature so far
    .

    The molecular pathogenesis of otulipenia is poorly understood
    .

    The defective OTULIN function leads to the up-regulation of M1 ubiquitin-mediated signaling and spontaneous NF-κB activation in bone marrow cells
    .

    Fibroblasts and monocytes from patients are sensitive to TNF-induced cell death, and an increase in apoptotic cells is observed in skin damage
    .

    Treatment with TNF and interleukin-1 (IL-1) inhibitors effectively reduces the burden of inflammation in patients with OTULIN deficiency
    .

    OTULIN dysfunction in mice causes type I interferon (IFN-I) to be produced in a way that depends on RIPK1
    .

    However, the effect of IFN-I on the inflammatory phenotype of patients has not been studied
    .

    In this study, it was demonstrated that IFN-I was activated in primary cells of patients with otulipenia, and the proteasome component was identified as a substrate for OTULIN-mediated linear deubiquitination
    .

    These studies expand the researchers' understanding of the pathophysiology of otulipenia and provide unexpected molecular connections between clinically relevant but genetically different autoinflammatory diseases
    .

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