Browsing by Author "Schaale, Katja Hrovat"
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Item Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24(2022) 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; Kile, Benjamin T.; DeNardo, Dominic; Sadler, Anthony J.; Poli, Cecilia; Krüger, Elke; Goldbach Mansky, Raphaela; Masters, Seth L.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.