The RNA-binding protein LUC7L2 mediates MITA/STING intron retention to negatively regulate innate antiviral response

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• The adaptor protein MITA (Mediator of IRF3 Activation), also known as STING (Stimulator of Interferon Genes), is crucial for DNA-triggered innate immunity.
• While post-translational modifications of MITA are studied, post-transcriptional regulation remains largely unexplored.
• Dysregulation of MITA is implicated in autoimmune diseases and cancer.

Purpose of the Study:

• To investigate the role of post-transcriptional mechanisms in regulating MITA.
• To identify novel regulators of the DNA virus-triggered innate immune response.
• To elucidate the function of the RNA-binding protein LUC7L2 in innate immunity.

Main Methods:

• Identification of RNA-binding proteins interacting with MITA.
• Analysis of LUC7L2 knockout mice response to Herpes Simplex Virus 1 (HSV-1) infection.
• Investigation of LUC7L2's mechanism of action on MITA pre-mRNA splicing and decay.
• Assessment of MITA protein levels and innate immune responses in LUC7L2-deficient cells.

Main Results:

• LUC7L2 was identified as a negative regulator of the DNA virus-induced innate immune response.
• LUC7L2-deficient mice showed resistance to HSV-1 infection and reduced viral loads.
• LUC7L2 binds to MITA pre-mRNA intron 3, inhibiting splicing and promoting nonsense-mediated decay, thus downregulating MITA protein.
• Cells lacking LUC7L2 exhibited elevated MITA levels and enhanced antiviral responses.
• HSV-1 infection induced LUC7L2 expression.

Conclusions:

• LUC7L2 acts as a negative post-transcriptional regulator of MITA.
• This study reveals a feedback mechanism controlling MITA-mediated innate immunity against viral and aberrant cellular DNA.
• LUC7L2 represents a potential therapeutic target for enhancing antiviral immunity.