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Proteasome disorders and inborn errors of immunity
(2023)
M. Cecilia Poli
<jats:title>Summary</jats:title><jats:p>Inborn errors of immunity (IEI) or primary immune deficiencies (PIDD) are caused by variants in genes encoding for molecules that are relevant to the innate or adaptive immune response. To date, defects in more than 450 different genes have been identified as causes of IEI, causing a constellation of heterogeneous clinical manifestations ranging from increased susceptibility to infection, to autoimmunity or autoinflammation. IEI that are mainly characterized by autoinflammation are broadly classified according to the inflammatory pathway that they predominantly perturb. Among autoinflammatory IEI are those characterized by the transcriptional upregulation of type I interferon genes and are referred to as interferonopathies. Within the spectrum of interferonopathies, genetic defects that affect the proteasome have been described to cause autoinflammatory disease and represent a growing area of investigation. This review is focused on describing the clinical, genetic, and molecular aspects of IEI associated with mutations that affect the proteasome and how the study of these diseases has contributed to delineate therapeutic interventions.</jats:p>
2Scopus© Citations 5
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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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Coronavirus disease 2019 in patients with inborn errors of immunity: An international study
(2021)
Isabelle Meyts
;
Giorgia Bucciol
;
Isabella Quinti
;
Bénédicte Neven
;
Alain Fischer
Scopus© Citations 309 3
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Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders
(2022)
Lisa R. Forbes
;
Olive S. Eckstein
;
Nitya Gulati
;
Erin C. Peckham-Gregory
;
Nmazuo W. Ozuah
14Scopus© Citations 15
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The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology Points to Consider for Diagnosis and Management of Autoinflammatory Type I Interferonopathies:
<scp>CANDLE</scp>
/
<scp>PRAAS</scp>
,
<scp>SAVI</scp>
, and
<scp>AGS</scp>
(2022)
Kader Cetin Gedik
;
Lovro Lamot
;
Micol Romano
;
Erkan Demirkaya
;
David Piskin
Scopus© Citations 36 1
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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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Inmunodeficiencia combinada severa: es tiempo de su detección precoz [Severe combined immunodeficiency: the time for newborn screening has come]
(2019)
POLI HARLOWE, MARIA CECILIA BERTA
8Scopus© Citations 3

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