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MITA oligomerization upon viral infection is dependent on its N-glycosylation mediated by DDOST

Yi Tu1, Xiu-Juan Yin1, Qian Liu1

  • 1State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, Wuhan University, Wuhan, China.

Plos Pathogens
|November 30, 2022
PubMed

Insights

Mediator of IRF3 activation (MITA) requires N-glycosylation by DDOST for immune function. Enhancing Ddost in mice boosts antiviral immunity and survival against herpes simplex virus encephalitis (HSE).

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • The mediator of IRF3 activation (MITA, also known as STING) is crucial for innate immune responses against cytosolic DNA.
  • MITA is a significant therapeutic target for cancer and autoimmune diseases.
  • The post-translational modifications regulating MITA's function are not fully understood.

Purpose of the Study:

  • To investigate the role of N-glycosylation in MITA activation and immune signaling.
  • To explore the specific enzyme responsible for MITA N-glycosylation.
  • To evaluate the therapeutic potential of modulating MITA glycosylation in viral infections.

Main Methods:

  • Investigated MITA N-glycosylation in endoplasmic reticulum (ER) upon DNA viral infection.
  • Utilized site-directed mutagenesis to identify DDOST-dependent glycosylation sites on MITA.
  • Assessed MITA oligomerization and immune function following mutation.
  • Examined the effect of Ddost expression on immune response and survival in mouse models of HSV-1 infection and HSE.

Main Results:

  • MITA undergoes DDOST-mediated N-glycosylation in the ER following DNA viral infection.
  • Mutation of DDOST-dependent N-glycosylation sites abrogated MITA oligomerization and its immune signaling capacity.
  • Increased Ddost expression in the mouse brain enhanced local antiviral immunity against HSV-1 and improved survival in experimental HSE.

Conclusions:

  • MITA activation is dependent on DDOST-mediated N-glycosylation.
  • This N-glycosylation is essential for MITA's oligomerization and subsequent immune function.
  • Targeting DDOST-mediated glycosylation offers a novel therapeutic strategy for viral encephalitis, particularly HSE.

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