Sophia Davidson, Chien-Hsiung Yu, Annemarie Steiner, Frédéric Ebstein, Paul J Baker, Valentina Jarur-Chamy, Katja Hrovat Schaale, Pawat Laohamonthonkul, Klara Kong, Dale J Calleja, Cassandra R Harapas, Katherine R Balka, Jacob Mitchell, Jacob T Jackson, Niall D Geoghegan, Fiona Moghaddas, Kelly L Rogers, Katrin D Mayer-Barber, Adriana A De Jesus, Dominic De Nardo, Benjamin T Kile, Anthony J Sadler, M Cecilia Poli, Elke Krüger, Raphaela Goldbach Mansky, Seth L Masters
Science immunology 2022 Feb 11Proteasome 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.
Sophia Davidson, Chien-Hsiung Yu, Annemarie Steiner, Frédéric Ebstein, Paul J Baker, Valentina Jarur-Chamy, Katja Hrovat Schaale, Pawat Laohamonthonkul, Klara Kong, Dale J Calleja, Cassandra R Harapas, Katherine R Balka, Jacob Mitchell, Jacob T Jackson, Niall D Geoghegan, Fiona Moghaddas, Kelly L Rogers, Katrin D Mayer-Barber, Adriana A De Jesus, Dominic De Nardo, Benjamin T Kile, Anthony J Sadler, M Cecilia Poli, Elke Krüger, Raphaela Goldbach Mansky, Seth L Masters. Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24. Science immunology. 2022 Feb 11;7(68):eabi6763
PMID: 35148201
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