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

Journal
Science Immunology
ISSN
2470-9468
Date Issued
2022
Author(s)
Sophia Davidson
Chien-Hsiung Yu
Annemarie Steiner
Frédéric Ebstein
Paul J. Baker
Valentina Jarur
Katja Hrovat Schaale
Pawat Laohamonthonkul
Klara Kong
Dale J. Calleja
Cassandra R. Harapas
Katherine R. Balka
Jacob Mitchell
Jacob T. Jackson
Niall D. Geoghegan
Fiona Moghaddas
Kelly L. Rogers
Katrin D. Mayer-Barber
Adriana A. De Jesus
Dominic De Nardo
Benjamin T. Kile
Anthony J. Sadler
M. Cecilia Poli
Elke Krüger
Raphaela Goldbach Mansky
Seth L. Masters
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85124577560
WoS ID
WOS:000810756000001
DOI
URL
URL Institutional Repository
Abstract
<jats:p>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.</jats:p>
Cite this document
Davidson, S., Yu, C.-H., Steiner, A., Ebstein, F., Baker, P. J., Jarur-Chamy, V., Hrovat Schaale, K., Laohamonthonkul, P., Kong, K., Calleja, D. J., Harapas, C. R., Balka, K. R., Mitchell, J., Jackson, J. T., Geoghegan, N. D., Moghaddas, F., Rogers, K. L., Mayer-Barber, K. D., De Jesus, A. A., … Masters, S. L. (2022). Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24. Science Immunology, 7(68), eabi6763. https://doi.org/10.1126/sciimmunol.abi6763
Project(s)
Subjects
animals

; 

cells, cultured

; 

eif-2 kinase

; 

humans

; 

immunity, innate

; 

interleukins

; 

mice

; 

mice, inbred c57bl

; 

mice, knockout

; 

alpha interferon

; 

beta interferon

; 

beta1 interferon

; 

bortezomib

; 

complementary dna

; 

delanzomib

; 

double stranded rna

; 

dynamin i

; 

gamma interferon inducible protein 10

; 

glycopeptidase

; 

initiation factor 2alpha

; 

interferon induced helicase c domain containing protein 1

; 

interleukin 24

; 

interleukin 6

; 

mitochondrial dna

; 

mitochondrial rna

; 

oprozomib

; 

pattern recognition receptor

; 

phosphoprotein phosphatase 1

; 

protein kinase r

; 

rna

; 

rna binding protein

; 

single guide rna

; 

stat1 protein

; 

tumor necrosis factor

; 

tumor necrosis factor receptor associated factor 2

; 

tumor necrosis factor receptor associated factor 3

; 

tumor necrosis factor receptor associated factor 5

; 

ubiquitin

; 

unclassified drug

; 

eif2ak2 protein, human

; 

interleukin derivative

; 

interleukin-24

; 

protein kinase r

; 

protein kinase r, mouse

; 

animal cell

; 

animal experiment

; 

animal model

; 

antiinflammatory activity

; 

article

; 

autoinflammatory disease

; 

cell differentiation

; 

controlled study

; 

crispr-cas9 system

; 

cytokine release

; 

disease association

; 

endoplasmic reticulum

; 

enzyme activation

; 

enzyme activity

; 

female

; 

fibroblast

; 

gene editing

; 

hematopoietic stem cell

; 

homeostasis

; 

human

; 

human cell

; 

ifnb1 gene

; 

il6 gene

; 

immunopathogenesis

; 

in vitro study

; 

in vivo study

; 

innate immunity

; 

male

; 

mouse

; 

mrna expression level

; 

nf kb signaling

; 

nonhuman

; 

protein degradation

; 

protein expression

; 

protein glycosylation

; 

protein induction

; 

protein misfolding

; 

protein phosphorylation

; 

protein protein interaction

; 

protein stability

; 

rna extraction

; 

tnf gene

; 

ubiquitination

; 

upregulation

; 

animal

; 

c57bl mouse

; 

cell culture

; 

immunology

; 

innate immunity

; 

knockout mouse