Cytoplasmic-translocated Ku70 senses intracellular DNA and mediates interferon-lambda1 induction

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Human Ku70, a nuclear protein, has been identified as a cytosolic DNA sensor.
• Ku70 translocates to the cytoplasm upon DNA stimulation, inducing interferon lambda1 (IFN-λ1) through a STING-dependent pathway.
• The precise mechanism of Ku70 translocation and its direct link to IFN-λ1 induction remain unclear.

Purpose of the Study:

• To elucidate the detailed mechanism of Ku70 cytoplasmic translocation.
• To investigate the correlation between Ku70 translocation and IFN-λ1 induction.
• To understand the role of Ku70 localization in sensing pathogenic DNA.

Main Methods:

• Observation of Ku70 translocation in DNA-triggered IFN-λ1-inducible cells.
• Infection with different strains of Herpes simplex virus type-1 (HSV-1).
• Kinetic analysis of Ku70 translocation post-DNA stimulation.
• Treatment with leptomycin B, a nuclear export inhibitor.
• Assessment of cellular acetylation status.

Main Results:

• Cytoplasmic translocation of Ku70 was observed only in DNA-triggered IFN-λ1-inducible cells.
• HSV-1 infection induced Ku70 translocation and IFN-λ1 induction in a strain-dependent manner (McKrae strain positive, MacIntyre strain negative).
• Ku70 translocation peaked at 6 hours post-DNA stimulation and was inhibited by leptomycin B, indicating it's an early, essential event.
• Enhanced cellular acetylation promoted Ku70 cytoplasmic accumulation and increased DNA-mediated IFN-λ1 induction.

Conclusions:

• Ku70 translocation is a critical and early step in cytosolic DNA sensing and subsequent IFN-λ1 induction.
• Ku70 acts as a versatile sensor, detecting pathogenic DNA in a localization-dependent manner.
• Cellular acetylation status influences Ku70's role in innate immune response to DNA.