MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Cyclic GMP-AMP synthase (cGAS) is a key sensor of cytosolic DNA, initiating innate immune responses via STING activation.
• Precise regulation of cGAS activity is crucial for maintaining immune homeostasis and preventing autoimmune disorders.

Purpose of the Study:

• To identify novel regulators of cGAS-mediated innate immunity.
• To elucidate the molecular mechanisms by which MARCH8 modulates cGAS signaling.

Main Methods:

• Overexpression, knockdown, and knockout of MARCH8 in cellular systems.
• Co-immunoprecipitation assays to study protein interactions.
• Ubiquitination assays to analyze post-translational modifications.
• Viral infection models (HSV-1) in mice.

Main Results:

• MARCH8 was identified as a negative regulator of cGAS signaling.
• MARCH8 directly interacts with cGAS and catalyzes its K63-linked polyubiquitylation at Lys411.
• MARCH8-mediated ubiquitination inhibits cGAS DNA binding, reduces cGAMP synthesis, and attenuates downstream immune signaling.
• Mice deficient in MARCH8 exhibit increased resistance to HSV-1 infection.

Conclusions:

• MARCH8 functions as an E3 ubiquitin ligase that negatively regulates cGAS by catalyzing its polyubiquitylation.
• This mechanism provides a novel pathway for fine-tuning the innate immune response to cytosolic DNA.
• Targeting MARCH8 could represent a therapeutic strategy for enhancing antiviral immunity.