Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24

<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>

Davidson, S., Yu, C.-H., Steiner, A., Ebstein, F., Baker, P. J., Jarur-Chamy, V., Hrovat Schaale, K., Laohamonthonkul, P., Kong, K., Calleja, D. J., Harapas, C. R., Balka, K. R., Mitchell, J., Jackson, J. T., Geoghegan, N. D., Moghaddas, F., Rogers, K. L., Mayer-Barber, K. D., De Jesus, A. A., … Masters, S. L. (2022). Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24. Science Immunology, 7(68), eabi6763. https://doi.org/10.1126/sciimmunol.abi6763