ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.
Subject(s)
Lymphohistiocytosis, Hemophagocytic/genetics , RNA-Binding Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Adolescent , Animals , Codon, Nonsense , Consanguinity , Cyclosporine/therapeutic use , Eosinophilia/genetics , Eosinophilia/immunology , Homozygote , Humans , Immunophenotyping , Immunosuppressive Agents/therapeutic use , Inducible T-Cell Co-Stimulator Protein/genetics , Inducible T-Cell Co-Stimulator Protein/immunology , Inducible T-Cell Co-Stimulator Protein/metabolism , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/immunology , Male , Mice , Monocytes/immunology , Receptors, OX40/genetics , Receptors, OX40/immunology , Receptors, OX40/metabolism , Recurrence , T-Lymphocytes/immunology , T-Lymphocytes, Regulatory/immunology , Ubiquitin-Protein Ligases/immunologyABSTRACT
The endoplasmic reticulum (ER) has a crucial role in the proper folding of proteins that are synthesized in the secretory pathway. Physiological and pathological conditions can induce accumulation of mis- or unfolded proteins in the ER lumen and thereby generate a state of cellular stress known as ER stress. The unfolded protein response aims at restoring protein-folding homeostasis, but turns into a toxic signal when ER stress is too severe or prolonged. ER stress-induced cellular dysfunction and death is associated with several human diseases, but the molecular mechanisms regulating death under unresolved ER stress are still unclear. We performed a siRNA-based screen to identify new regulators of ER stress-induced death and found that repression of the Carney complex-associated protein PRKAR1A specifically protected the cells from ER stress-induced apoptosis, and not from apoptosis induced by etoposide or TNF. We demonstrate that the protection results from PKA activation and associate it, at least in part, with the phosphorylation-mediated inhibition of the PKA substrate Drp1 (dynamin-related protein 1). Our results therefore provide new information on the complex regulation of cellular death under ER stress conditions and bring new insights on the conditions that regulate the pro- versus anti-death functions of PKA.
