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Author: search.filters.author.Elke KrügerSubject: search.filters.subject.immunology

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    HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related autoinflammatory disease
    (2021)
    Caridad Martinez
    ;
    Frédéric Ebstein
    ;
    Sarah K. Nicholas
    ;
    Marietta De Guzman
    ;
    Lisa R. Forbes
      8Scopus© Citations 21
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    Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24
    (2022)
    Sophia Davidson
    ;
    Chien-Hsiung Yu
    ;
    Annemarie Steiner
    ;
    Frédéric Ebstein
    ;
    Paul J. Baker
    <jats:p>Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor–induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum–associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.</jats:p>
    Scopus© Citations 55  3
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      11Scopus© Citations 71