Journal
SCIENCE IMMUNOLOGY
Volume 7, Issue 68, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abi6763
Keywords
-
Categories
Funding
- National Health and Medical Research Council (NHMRC) [1144282, 1142354, 1099262]
- Sylvia and Charles Viertel Foundation
- HHMI-Wellcome International Research Scholarship
- Glaxosmithkline
- NHMRC [GNT1143412, GNT2003756]
- German Research Foundation [SFBTR 167, RTG 2719/B4]
- FONDECYT [11181222]
- intramural research program of NIAID
- Wellcome Trust [208694/Z/17/Z]
- Wellcome Trust [208694/Z/17/Z] Funding Source: Wellcome Trust
Ask authors/readers for more resources
This study identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.
Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-alpha beta) and NF-kappa B 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 eIF2 alpha, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available