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MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation

Xikang Yang1,2,3, Chengrui Shi1,2,3, Hongpeng Li1,2,3,4

  • 1School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.

Science Signaling
|May 3, 2022
PubMed

Insights

The E3 ubiquitin ligase MARCH8 negatively regulates cyclic GMP-AMP synthase (cGAS) signaling by polyubiquitylating cGAS, thereby dampening the innate immune response to DNA. MARCH8 deficiency enhances immunity and reduces susceptibility to viral infections.

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.

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