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USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA

Liya Ye1,2, Qiang Zhang1,2, Tianzi Liuyu1,2

  • 1Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.

Plos Pathogens
|April 4, 2019
PubMed

Insights

USP49 deubiquitinates MITA, a key protein in antiviral responses. This action dampens the immune system

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Mediator of IRF3 activation (MITA) is crucial for innate immunity against viral infections.
  • MITA's activity is tightly controlled by ubiquitination and deubiquitination processes.
  • Dysregulation of MITA signaling is implicated in autoimmune diseases and cancer.

Purpose of the Study:

  • To investigate the role of USP49 in regulating MITA-mediated antiviral signaling.
  • To elucidate the deubiquitinase activity of USP49 on MITA following HSV-1 infection.
  • To understand how USP49 impacts innate immune responses and viral replication.

Main Methods:

  • Co-immunoprecipitation assays to detect USP49-MITA interaction.
  • Western blotting to analyze ubiquitination status of MITA.
  • Quantitative PCR and ELISA to measure cytokine production.
  • Viral replication assays and mouse infection models (Usp49-/- mice).

Main Results:

  • USP49 directly interacts with and deubiquitinates MITA after HSV-1 infection.
  • USP49 deficiency enhances type I interferon and pro-inflammatory cytokine production.
  • USP49 knockout or knockdown impairs HSV-1 replication and confers resistance to lethal HSV-1 infection in mice.
  • USP49 removes K63-linked ubiquitin chains from MITA, inhibiting its aggregation and TBK1 recruitment.

Conclusions:

  • USP49 acts as a negative regulator of innate antiviral immunity by deubiquitinating MITA.
  • USP49 plays a critical role in terminating cellular antiviral responses post-HSV-1 infection.
  • Targeting USP49 may offer therapeutic strategies for viral infections and related immune disorders.

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