TY - JOUR
T1 - Type I IFN is siloed in endosomes
AU - Altman, Jennie B.
AU - Taft, Justin
AU - Wedeking, Tim
AU - Gruber, Conor N.
AU - Holtmannspötter, Michael
AU - Piehler, Jacob
AU - Bogunovic, Dusan
N1 - Funding Information:
We thank Allison Sowa and Bill Janssen from the Mount Sinai Microscopy Core and Ludovic Debure and Dr. Thomas Wis-niewski at New York University for their assistance with SiMoA (Grants AG08051 and R01AF058267). Funding sources are as follows: Deutsche Forschungsgemeinschaft to J.P. (Grants PI 405/10 and PI 405/14), National Institute of Allergy and Infectious Diseases to D.B. (Grant R01AI127372), and Virus-Host Interactions training grant to J.B.A. (Grant 5T32AI007647-17).
Funding Information:
Forschungsgemeinschaft to J.P. (Grants PI 405/10 and PI 405/14), National Institute of Allergy and Infectious Diseases to D.B. (Grant R01AI127372), and Virus-Host Interactions training grant to J.B.A. (Grant 5T32AI007647-17).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/7/28
Y1 - 2020/7/28
N2 - 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.
AB - 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.
KW - Cytokine retention
KW - Endosome
KW - Type I interferon
UR - http://www.scopus.com/inward/record.url?scp=85088879639&partnerID=8YFLogxK
U2 - 10.1073/pnas.1921324117
DO - 10.1073/pnas.1921324117
M3 - Article
C2 - 32665439
AN - SCOPUS:85088879639
SN - 0027-8424
VL - 117
SP - 17510
EP - 17512
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -