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

S Davidson; CH Yu; A Steiner; F Ebstein; PJ Baker; V Jarur-Chamy; KH Schaale; P Laohamonthonkul; K Kong; DJ Calleja; CR Harapas; KR Balka; J Mitchell; JT Jackson; ND Geoghegan; F Moghaddas; KL Rogers; KD Mayer-Barber; AA De Jesus; D De Nardo; BT Kile; AJ Sadler; MC Poli; E Krüger; RG Mansky; SL Masters

Journal article

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

S Davidson, CH Yu, A Steiner, F Ebstein, PJ Baker, V Jarur-Chamy, KH Schaale, P Laohamonthonkul, K Kong, DJ Calleja, CR Harapas, KR Balka, J Mitchell, JT Jackson, ND Geoghegan, F Moghaddas, KL Rogers, KD Mayer-Barber, AA De Jesus, D De Nardo Show all

Science Immunology | Published : 2022

DOI: 10.1126/sciimmunol.abi6763

Abstract

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..

View full abstract

University of Melbourne Researchers

Annemarie Steiner Author

Niall Geoghegan Author

Kelly Rogers Author

Seth Masters Author

Grants

Awarded by National Institute of Allergy and Infectious Diseases

Funding Acknowledgements

S.L.M acknowledges funding from the National Health and Medical Research Council (NHMRC) grants (1144282, 1142354, and 1099262), The Sylvia and Charles Viertel Foundation, HHMI-Wellcome International Research Scholarship, and Glaxosmithkline. S.D. acknowledges funding from NHMRC grants (GNT1143412 and GNT2003756). E.K. acknowledges funding from the German Research Foundation (SFBTR 167; RTG 2719/B4). V.J.-C. acknowledges funding from FONDECYT no. 11181222. This work was supported in part by the intramural research program of NIAID (to K.D.M.-B., P.J.B, R.G.M., A.A.D.J., and A.M.). This research was funded in part by the Wellcome Trust (208694/Z/17/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.