Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24
- Author(s)
- Davidson, 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;
- Details
- Publication Year 2022-02-11,Volume 7,Issue #68,Page eabi6763
- Journal Title
- Science Immunology
- 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-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.
- Publisher
- AAAS
- Research Division(s)
- Inflammation; Advanced Technology And Biology; Immunology; Ubiquitin Signalling
- PubMed ID
- 35148201
- Publisher's Version
- https://doi.org/10.1126/sciimmunol.abi6763
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-02-18 10:38:00
Last Modified: 2022-02-18 11:02:17