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.De Nardo, D.et al.2022-07-262022-07-262022Science Immunology, 2022; 7(68):eabi6763-1-eabi6763-?2470-94682470-9468https://hdl.handle.net/2440/135864Proteasome 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.enCopyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Cells, CulturedAnimalsMice, Inbred C57BLMice, KnockoutHumansMiceeIF-2 KinaseInterleukinsImmunity, InnateCells, CulturedAnimalsMice, Inbred C57BLMice, KnockoutHumansMiceeIF-2 KinaseInterleukinsImmunity, InnateJournal article10.1126/sciimmunol.abi67632022-07-21602501Kile, B.T. [0000-0002-8836-8947]