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Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
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USP44 positively regulates innate immune response to DNA viruses through deubiquitinating MITA

Hong-Yan Zhang1,2, Bo-Wei Liao1,2, Zhi-Sheng Xu1

  • 1Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.

Plos Pathogens
|January 23, 2020
PubMed

Insights

The deubiquitinating enzyme USP44 positively regulates MITA, a key protein in antiviral immunity. USP44 prevents MITA degradation, enhancing the immune response against DNA viruses like HSV-1.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Mediator of IRF3 activation (MITA/STING) is crucial for sensing DNA virus infection and initiating innate antiviral responses.
  • MITA activity is tightly regulated by post-translational modifications, including polyubiquitination.

Purpose of the Study:

  • To identify deubiquitinating enzymes that regulate MITA.
  • To elucidate the role of USP44 in the innate immune response against DNA viruses.

Main Methods:

  • Co-immunoprecipitation to assess USP44 recruitment to MITA.
  • Western blotting to detect MITA ubiquitination and degradation.
  • Analysis of type I interferon and cytokine induction in USP44-deficient cells.
  • HSV-1 infection studies in Usp44-/- mice.

Main Results:

  • USP44 was identified as a positive regulator of MITA.
  • USP44 removes K48-linked polyubiquitin chains from MITA at K236, preventing its proteasomal degradation.
  • USP44 deficiency accelerated MITA degradation, reduced type I interferon and cytokine production, and increased susceptibility to HSV-1 infection in mice.

Conclusions:

  • USP44 is a critical deubiquitinating enzyme that positively regulates MITA stability and function.
  • USP44 plays a specific role in innate immunity against DNA viruses, particularly HSV-1.
  • USP44 represents a potential therapeutic target for enhancing antiviral immunity.

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