作者
Sophia Davidson,Chien-Hsiung Yu,Annemarie Steiner,Frédéric Ebstein,Paul K. Baker,Valentina Jarur-Chamy,Katja Hrovat Schaale,Pawat Laohamonthonkul,Klara Kong,Dale J. Calleja,Cassandra R. Harapas,Katherine R. Balka,Jacob John Mitchell,Jacob T. Jackson,Niall D. Geoghegan,Fiona Moghaddas,Kelly L. Rogers,Katrin D. Mayer-Barber,Adriana Almeida de Jesus,Dominic De Nardo,Benjamin T. Kile,Anthony J. Sadler,M. Poli,Elke Krüger,Raphaela Goldbach-Mansky,Seth L. Masters
摘要
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.