Downregulation of the IFNAR1 chain of type 1 interferon receptor contributes to the maintenance of the haematopoietic stem cells

Abstract

Recent studies demonstrated that prolonged exposure of haematopoietic stem cells (HSCs) to type I interferons (IFN) stimulates HSCs entrance into cell cycle, continuous proliferation and eventual exhaustion, which could be prevented by ablation of the Ifnar1 chain of IFN receptor. Given that levels IFNAR1 expression can be robustly affected by IFN-independent ubiquitination and downregulation of IFNAR1 in response to activation of protein kinases such as protein kinase R-like endoplasmic reticulum kinase (PERK) and casein kinase 1α (CK1α), we aimed to determine the role of IFNAR1 downregulation in the maintenance of HSCs. Mice harboring the ubiquitination-deficient Ifnar1S526A allele displayed greater levels of haematopoietic cell progenitors but reduced numbers of the long-term HSCs compared with wild type mice and animals lacking Ifnar1. Studies using competitive bone marrow repopulation assays showed that CK1α (but not PERK) is essential for the long-term HSCs function. Concurrent ablation of Ifnar1 led to a modest attenuation of the CK1α-null phenotype indicating that, although other CK1α targets are likely to be important, IFNAR1 downregulation can contribute to the maintenance of the HSCs function.