Davidson, SophiaYu, Chien-HsiungSteiner, AnnemarieEbstein, FrédéricBaker, Paul J.Jarur-Chamy, ValentinaSchaale, Katja HrovatLaohamonthonkul, PawatKong, KlaraCalleja, Dale J.Harapas, Cassandra R.Balka, Katherine R.Mitchell, JacobJackson, Jacob T.Geoghegan, Niall D.Moghaddas, FionaRogers, Kelly L.Mayer-Barber, Katrin D.De Jesus, AdrianaKile, Benjamin T.DeNardo, DominicSadler, Anthony J.Poli, CeciliaKrüger, ElkeGoldbach Mansky, RaphaelaMasters, Seth L.2022-04-062022-04-062022Davidson S, Yu CH, Steiner A, Ebstein F, Baker PJ, Jarur-Chamy V, Hrovat Schaale K, Laohamonthonkul P, Kong K, Calleja DJ, Harapas CR, Balka KR, Mitchell J, Jackson JT, Geoghegan ND, Moghaddas F, Rogers KL, Mayer-Barber KD, De Jesus AA, De Nardo D, Kile BT, Sadler AJ, Poli MC, Krüger E, Goldbach Mansky R, Masters SL. Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24. Sci Immunol. 2022 Feb 11;7(68):eabi6763. doi: 10.1126/sciimmunol.abi6763.https://doi.org/10.1126/sciimmunol.abi6763http://hdl.handle.net/11447/5953Proteasome 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.enStressAutoinflammatory diseasePKRProtein kinase RArticle