| Autor: |
Davidson, Sophia, Yu, Chien-Hsiung, Steiner, Annemarie, Ebstein, Frédéric, Baker, Paul J., Jarur-Chamy, Valentina, Schaale, Katja Hrovat, Laohamonthonkul, Pawat, Kong, Klara, Calleja, Dale J., Harapas, Cassandra R., Balka, Katherine R., Mitchell, Jacob, Jackson, Jacob T., Geoghegan, Niall D., Moghaddas, Fiona, Rogers, Kelly L., Mayer-Barber, Katrin D., De Jesus, Adriana A., De Nardo, Dominic |
| Zdroj: |
Science Immunology; 2022, Vol. 7 Issue 68, p1-14, 14p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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