Type I IFN is siloed in endosomes.

Area of Science:

• Immunology
• Cell Biology

Background:

• Type I Interferon (IFN-I) signaling is typically considered transient.
• However, observed long-term effects of IFN-I suggest a persistent mechanism.
• Existing explanations focus on long-lived downstream molecules.

Purpose of the Study:

• To elucidate the mechanism behind the prolonged effects of Type I Interferon.
• To investigate the intracellular fate and signaling capacity of IFN-I after receptor binding.

Main Methods:

• Fluorescence microscopy
• Electron microscopy
• Analysis of IFN-I signaling in the presence and absence of negative regulators (ISG15, USP18)

Main Results:

• Type I IFN is sequestered into intracellular endosomal compartments, termed "IFN silos."
• These "IFN silos" remain intact for days.
• Siloed IFN-I can continue to signal from endosomes, particularly when negative regulators like ISG15 or USP18 are deficient.

Conclusions:

• A novel mechanism for sustained Type I IFN activity involves intracellular "IFN silos."
• This mechanism explains long-term IFN-I effects and may be relevant to IFN-I therapies.
• Deficiency in negative regulators can lead to persistent IFN-I signaling from these intracellular compartments, potentially contributing to interferonopathies.