PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Altman JB, Taft J, Wedeking T, Gruber CN, Holtmannspötter M, Piehler J and Bogunovic D.

PNAS July 28, 2020 117 (30) 17510-17512

DOI: https://doi.org/10.1073/pnas.1921324117

Abstract

Type I IFN (IFN-I) is thought to be rapidly internalized and degraded following binding to its receptor and initiation of signaling. However, many studies report the persistent effects mediated by IFN-I for days or even weeks, both ex vivo and in vivo. These long-lasting effects are attributed to downstream signaling molecules or induced effectors having a long half-life, particularly in specific cell types. Here, we describe a mechanism explaining the long-term effects of IFN-I. Following receptor binding, IFN-I is siloed into endosomal compartments. These intracellular “IFN silos” persist for days and can be visualized by fluorescence and electron microscopy. However, they are largely dormant functionally, due to IFN-I−induced negative regulators. By contrast, in individuals lacking these negative regulators, such as ISG15 or USP18, this siloed IFN-I can continue to signal from within the endosome. This mechanism may underlie the long-term effects of IFN-I therapy and may contribute to the pathophysiology of type I interferonopathies.

Type I IFN (IFN-I) is a potent antiviral and inflammatory cytokine, with a relatively short half-life .It disappears from the plasma several hours after intramuscular administration. Even pegylated IFN-I has a half-life of just 2 d in humans. Nevertheless, IFN-I has long-term functional effects. For example, expression of OAS1, an IFN-stimulated gene (ISG), remains close to peak levels for 1 wk in humans given pegylated IFN-I. Similarly, following influenza infection and resolution in mice, bone marrow leukocytes express antiviral genes and are resistant to influenza infection despite lack of detection of IFN-I in the bone marrow or serum on enzyme-linked immunosorbent assay. Likewise, individuals lacking ISG15 or USP18, both key negative regulators of IFN-I, have high levels of ISGs in peripheral blood mononuclear cells (PBMCs), as expected, but circulating IFN-I is only detectable in half of ISG15-deficient individuals, highlighting the potency of IFN-I. Here, we explore the cellular mechanisms governing this human phenotype.