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MARCH8-mediated ubiquitination regulates expression of the antiviral protein IFITM3

Liang Wei1, Fei Zhao1, Xiaoman Liu1

  • 1Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China; NHC Key Laboratory of Systems Biology of Pathogens, National Institute of Pathogen Biology and Center for AIDS Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.

The Journal of Biological Chemistry
|November 6, 2025
PubMed

Insights

The Membrane-Associated RING-CH 8 (MARCH8) E3 ligase targets the antiviral protein IFITM3 for degradation. This process enhances viral entry, revealing a new mechanism in innate immunity regulation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Membrane-Associated RING-CH (MARCH) E3 ligases regulate protein stability and innate immunity.
  • Interferon-induced transmembrane protein 3 (IFITM3) is a key antiviral effector protein.

Purpose of the Study:

  • To identify novel substrates of MARCH8.
  • To elucidate the mechanism by which MARCH8 regulates IFITM3.
  • To determine the functional consequences of the MARCH8-IFITM3 interaction on antiviral responses.

Main Methods:

  • Coimmunoprecipitation assays.
  • Liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • Western blotting and immunofluorescence in wild-type and MARCH8-knockout cells.

Main Results:

  • IFITM3 was identified as a novel substrate of MARCH8.
  • MARCH8 mediates K63-linked polyubiquitination of IFITM3 at lysine 24, promoting lysosomal degradation.
  • MARCH8 deficiency leads to IFITM3 accumulation at the plasma membrane and increased susceptibility to viral infection.
  • MARCH8 expression attenuated IFITM3-mediated restriction of vesicular stomatitis virus and influenza A virus.

Conclusions:

  • MARCH8 regulates the trafficking and turnover of the antiviral protein IFITM3.
  • This interaction represents a novel mechanism by which MARCH8 modulates innate immunity.
  • MARCH8 plays a critical role in controlling cellular susceptibility to viral pathogens.
Keywords:
E3 ligaseIFITM3IFNMARCH8ubiquitinationvirus infection

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