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

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dc.contributor.authorDavidson, Sophia
dc.contributor.authorYu, Chien-Hsiung
dc.contributor.authorSteiner, Annemarie
dc.contributor.authorEbstein, Frédéric
dc.contributor.authorBaker, Paul J.
dc.contributor.authorJarur-Chamy, Valentina
dc.contributor.authorSchaale, Katja Hrovat
dc.contributor.authorLaohamonthonkul, Pawat
dc.contributor.authorKong, Klara
dc.contributor.authorCalleja, Dale J.
dc.contributor.authorHarapas, Cassandra R.
dc.contributor.authorBalka, Katherine R.
dc.contributor.authorMitchell, Jacob
dc.contributor.authorJackson, Jacob T.
dc.contributor.authorGeoghegan, Niall D.
dc.contributor.authorMoghaddas, Fiona
dc.contributor.authorRogers, Kelly L.
dc.contributor.authorMayer-Barber, Katrin D.
dc.contributor.authorDe Jesus, Adriana
dc.contributor.authorKile, Benjamin T.
dc.contributor.authorDeNardo, Dominic
dc.contributor.authorSadler, Anthony J.
dc.contributor.authorPoli, Cecilia
dc.contributor.authorKrüger, Elke
dc.contributor.authorGoldbach Mansky, Raphaela
dc.contributor.authorMasters, Seth L.
dc.date.accessioned2022-04-06T21:06:33Z
dc.date.available2022-04-06T21:06:33Z
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.es
dc.description.versionVersión Publicadaes
dc.identifier.citationDavidson 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.es
dc.identifier.urihttps://doi.org/10.1126/sciimmunol.abi6763es
dc.identifier.urihttp://hdl.handle.net/11447/5953
dc.language.isoenes
dc.subjectStresses
dc.subjectAutoinflammatory diseasees
dc.subjectPKRes
dc.subjectProtein kinase Res
dc.titleProtein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24es
dc.typeArticlees
dcterms.sourceScience Immunologyes

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