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

蛋白激酶R 蛋白酶体 细胞生物学 生物 EIF-2激酶 干扰素 未折叠蛋白反应 先天免疫系统 肿瘤坏死因子α 蛋白激酶A 激酶 炎症 免疫系统 内质网 免疫学 丝裂原活化蛋白激酶激酶 细胞周期蛋白依赖激酶2
作者
Sophia Davidson,Chien-Hsiung Yu,Annemarie Steiner,Frédéric Ebstein,Paul K. Baker,Valentina Jarur-Chamy,Katja Hrovat Schaale,Pawat Laohamonthonkul,Klara Kong,Dale J. Calleja,Cassandra R. Harapas,Katherine R. Balka,Jacob John Mitchell,Jacob T. Jackson,Niall D. Geoghegan,Fiona Moghaddas,Kelly L. Rogers,Katrin D. Mayer-Barber,Adriana Almeida de Jesus,Dominic De Nardo,Benjamin T. Kile,Anthony J. Sadler,M. Poli,Elke Krüger,Raphaela Goldbach-Mansky,Seth L. Masters
出处
期刊:Science immunology [American Association for the Advancement of Science (AAAS)]
卷期号:7 (68) 被引量:9
标识
DOI:10.1126/sciimmunol.abi6763
摘要

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.
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