SNX8 modulates innate immune response to DNA virus by mediating trafficking and activation of MITA

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• MITA (Mediator of IRF3 activation), also known as STING (Stimulator of Interferon Genes), is a key adaptor protein in the innate immune response to cytosolic DNA.
• The cellular trafficking of MITA from the endoplasmic reticulum (ER) to perinuclear microsomes is essential for its activation and initiating the innate antiviral response following DNA virus infection.

Purpose of the Study:

• To investigate the role of SNX8 (Sorting Nexin 8) in the DNA-triggered innate immune response.
• To elucidate the mechanism by which SNX8 influences MITA trafficking and activation.

Main Methods:

• Utilized knockout mice lacking SNX8 (Snx8-/-) for infection studies with the DNA virus HSV-1.
• Assessed serum cytokine levels, viral titers in the brain, and animal lethality in Snx8-/- mice compared to controls.
• Investigated the molecular mechanism of SNX8 action, including its interaction with VPS34 and MITA.

Main Results:

• Snx8-/- mice showed diminished serum cytokine levels and increased viral loads in the brain after HSV-1 infection, leading to higher mortality.
• SNX8 was identified as a critical component in the DNA-triggered induction of downstream effector genes and the overall innate immune response.
• Mechanistically, SNX8 was found to recruit the VPS34 (Vacuolar protein sorting 34) kinase to MITA, a process vital for MITA's ER to perinuclear trafficking.

Conclusions:

• SNX8 plays a vital role in the innate immune defense against DNA viruses by regulating MITA trafficking.
• The SNX8-VPS34-MITA axis is a critical pathway for initiating antiviral responses upon detection of cytosolic DNA.
• Targeting SNX8 could represent a novel therapeutic strategy for enhancing innate immunity against DNA viral infections.