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

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.

Screening Biomarkers for Systemic Lupus Erythematosus Based on Machine Learning and Exploring Their Expression Correlations With the Ratios of Various Immune Cells

“…Besides, EIF2AK2 selectively regulates the transcription of genes functioning in immune response in SLE (39). In proteasomeassociated autoinflammatory cell models, the activation of EIF2AK2 is discovered responding to the decreased proteasome function (40). Numerous studies have demonstrated the indispensable role of IFI27 (Interferon (IFN)-a-inducible protein 27) in SLE (41)(42)(43).…”

Immunoproteasomes control activation of innate immune signaling and microglial function

“…Davidson et al. demonstrate that PKR drives induction of type I IFN response in proteasome associated autoinflammatory syndromes depending on its cytosolic interactor IL-24 accumulation ( 69 ). We suggest that PKR may drive induction of type I IFN signaling in IP impaired human microglia depending on IL-24 accumulation.…”

Immunogenic cell death triggered by impaired deubiquitination in multiple myeloma relies on dysregulated type I interferon signaling

“…Our data further suggest that type I IFN under these conditions is not driven by host nucleic acids cells, since inhibition of the nucleic acid receptors TLR3 and STING by dsRNA/TLR3 antagonist and H-151, r e s p e c t i v e l y h a d n o d i s c e r n a b l e i m p a c t o n S T A T 1 phosphorylation and/or ISG expression profile (Figures 3B, S8, S9). Given the described ability of the UPR/ISR to induce sterile inflammation (82), we next asked whether it participated in the PR619-mediated type I IFN response in NCI-H929 cells. To address this point, we took advantage of commercially available inhibitors targeting the UPR/ISR at different levels including 4µ8C, C16, A92 and guanabenz which inhibit IRE1a, PKR, GCN2 and eIF2a dephosphorylation, respectively (84)(85)(86).…”