ArticleScience immunology2022
Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24.
Article in Science immunology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 62 citations in OpenAlex.
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- Editing regulatory network in non-small cell lung cancer: implications for immunity and metastasis.Human genomics · 2026Article
- Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly.American journal of human genetics · 2026Article
- Cell autonomous inflammation in VEXAS is mediated by cGAS-STING.bioRxiv : the preprint server for biology · 2026Article
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- Molecular mechanisms in rare proteasomopathies.EULAR rheumatology open · 2026Review
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- Interleukin-24 in type 2 immune diseases.Frontiers in immunology · 2026Review
- Deciphering the multifaceted role of double-stranded RNA sensor protein kinase R: pathophysiological function beyond the antiviral response.RNA biology · 2025Review
- Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.Nature communications · 2025Article
- The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Interferons in health and disease.Cell · 2025Review
- Proteasome dysfunction in T cells causes immunodeficiency via cell cycle disruption and apoptosis.International immunology · 2025Article
- Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology.Neurobiology of disease · 2025Article
- Primary disorders of polyubiquitination: Dual roles in autoinflammation and immunodeficiency.The Journal of experimental medicine · 2025Review
- STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.Molecular cell · 2025Article
- PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration.Nature communications · 2025Article
- Unleashing the Potential of Metal Ions in cGAS-STING Activation: Advancing Nanomaterial-Based Tumor Immunotherapy.ACS omega · 2025Review
- Emerging concepts and treatments in autoinflammatory interferonopathies and monogenic systemic lupus erythematosus.Nature reviews. Rheumatology · 2025Review
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26 authors at 8 institutions in 4 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.