Polyglutamine binding protein 1 (PQBP1) inhibits innate immune responses to cytosolic DNA

Area of Science:

• Immunology
• Molecular Biology
• Cellular Biology

Background:

• Immune sensing of cytosolic DNA is crucial for pathogen defense and maintaining homeostasis.
• Interferon-γ-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) are key DNA sensors involved in innate immunity.
• Polyglutamine binding protein 1 (PQBP1) has been implicated in type I interferon production during retroviral infection.

Purpose of the Study:

• To investigate the roles of IFI16 and cGAS in sensing cytosolic DNA.
• To elucidate the function of PQBP1 in cytosolic DNA sensing pathways.
• To determine the clinical relevance of PQBP1, IFI16, and cGAS expression in cancer patients.

Main Methods:

• Synergistic induction of IFNb transcriptional activity by IFI16 and cGAS in response to cytosolic DNA.
• Co-immunoprecipitation assays to assess PQBP1 association with IFI16 and cGAS in THP-1 cells.
• CRISPR-Cas9 knockout of PQBP1 in THP-1 cells and overexpression studies in HEK293T cells.
• Correlation analysis of PQBP1, cGAS, and IFI16 expression with patient survival data.

Main Results:

• IFI16 and cGAS synergistically induce IFNb transcription upon sensing cytosolic DNA.
• PQBP1 physically associates with both IFI16 and cGAS.
• PQBP1 knockout enhances type I interferon production in response to cytosolic DNA or DNA damage, contrary to its role in retroviral infection.
• PQBP1 overexpression suppresses IFI16/cGAS-mediated IFNb transcription.
• Low PQBP1 expression in cancer patients correlates with improved survival, unlike cGAS or IFI16.

Conclusions:

• PQBP1 acts as an inhibitor of the IFI16/cGAS signaling pathway in response to cytosolic DNA.
• The function of PQBP1 in cytosolic DNA sensing is distinct from its role in retroviral infection.
• PQBP1 expression levels have prognostic implications in human cancers, suggesting a potential therapeutic target.