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

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dc.contributor.authorDavidson, S.
dc.contributor.authorYu, C.-H.
dc.contributor.authorSteiner, A.
dc.contributor.authorEbstein, F.
dc.contributor.authorBaker, P.J.
dc.contributor.authorJarur-Chamy, V.
dc.contributor.authorHrovat Schaale, K.
dc.contributor.authorLaohamonthonkul, P.
dc.contributor.authorKong, K.
dc.contributor.authorCalleja, D.J.
dc.contributor.authorHarapas, C.R.
dc.contributor.authorBalka, K.R.
dc.contributor.authorMitchell, J.
dc.contributor.authorJackson, J.T.
dc.contributor.authorGeoghegan, N.D.
dc.contributor.authorMoghaddas, F.
dc.contributor.authorRogers, K.L.
dc.contributor.authorMayer-Barber, K.D.
dc.contributor.authorDe Jesus, A.A.
dc.contributor.authorDe Nardo, D.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.abstractProteasome 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.
dc.description.statementofresponsibilitySophia Davidson, Chien-Hsiung Yu, Annemarie Steiner, Frederic Ebstein, Paul J. Baker, Valentina Jarur-Chamy, Katja Hrovat Schaale, Pawat Laohamonthonkul, Klara Long, Dale J. Calleja, Cassandra R. Harapas, Katherine R. Balka, Jacob Mitchell, Jacob T. Jackson, Niall D. Geohegan, Fiona Moghaddas, Kelly L. Rogers, Katrin D. Mayer-Barber, Adriana A. De Jesus, Dominic De Nardo, Benjamin T. Kile, Anthony J. Sadler, M. Cecilia Poli, Elke Kruger, Raphaela Goldbach Mansky and Seth L. Masters
dc.identifier.citationScience Immunology, 2022; 7(68):eabi6763-1-eabi6763-?
dc.identifier.doi10.1126/sciimmunol.abi6763
dc.identifier.issn2470-9468
dc.identifier.issn2470-9468
dc.identifier.orcidKile, B.T. [0000-0002-8836-8947]
dc.identifier.urihttps://hdl.handle.net/2440/135864
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1144282
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1142354
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1099262
dc.rightsCopyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
dc.source.urihttps://doi.org/10.1126/sciimmunol.abi6763
dc.subjectCells, Cultured
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjecteIF-2 Kinase
dc.subjectInterleukins
dc.subjectImmunity, Innate
dc.subject.meshCells, Cultured
dc.subject.meshAnimals
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Knockout
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.mesheIF-2 Kinase
dc.subject.meshInterleukins
dc.subject.meshImmunity, Innate
dc.titleProtein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24
dc.typeJournal article
pubs.publication-statusPublished

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