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HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related autoinflammatory disease
(2021)
Caridad Martinez
;
Frédéric Ebstein
;
Sarah K. Nicholas
;
Marietta De Guzman
;
Lisa R. Forbes
8Scopus© Citations 21
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Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24
(2022)
Sophia Davidson
;
Chien-Hsiung Yu
;
Annemarie Steiner
;
Frédéric Ebstein
;
Paul J. Baker
<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>
Scopus© Citations 55 3
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Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)
(2019)
Frédéric Ebstein
;
María Cecilia Poli Harlowe
;
Maja Studencka-Turski
;
Elke Krüger
11Scopus© Citations 71
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Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome
(2018)
POLI HARLOWE, MARIA CECILIA BERTA
;
Frédéric Ebstein
;
Sarah K. Nicholas
;
Marietta M. de Guzman
;
Lisa R. Forbes
1Scopus© Citations 142

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