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The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling

Young-Suk Yoo1, Yong-Yea Park2, Jae-Hoon Kim3

  • 11] Department of Biochemistry, Ajou University School of Medicine, Graduate School of Ajou University, Suwon 443-380, Korea [2] Department of Biological Sciences, Graduate School of Ajou University, Suwon 443-380, Korea.

Nature Communications
|August 7, 2015
PubMed

Insights

The E3 ligase MARCH5 protein resolves mitochondrial antiviral signalling (MAVS) aggregates, preventing excessive immune responses during viral infections. This discovery offers new insights into innate immunity regulation.

Area of Science:

  • Immunology
  • Cell Biology
  • Virology

Background:

  • Mitochondria are crucial platforms for innate immune responses.
  • The mitochondrial antiviral signalling (MAVS) protein aggregates to induce type-I interferon during viral infections.
  • Persistent MAVS signalling can cause host immunopathology, but mechanisms for resolving MAVS aggregates are unknown.

Purpose of the Study:

  • To identify regulators of MAVS aggregate resolution.
  • To investigate the role of E3 ligases in MAVS signalling pathways.
  • To understand how excessive antiviral signalling is controlled.

Main Methods:

  • Utilized March5(+/-) mice and MARCH5-deficient immune cells.
  • Investigated protein-protein interactions between MARCH5 and MAVS during viral stimulation.
  • Analyzed the ubiquitination and proteasomal degradation of MAVS.
  • Assessed viral replication and type-I interferon responses.

Main Results:

  • MARCH5 was identified as a negative regulator of MAVS aggregates.
  • MARCH5 deficiency led to reduced viral replication and enhanced type-I interferon responses.
  • MARCH5 specifically binds to MAVS aggregates during viral infection.
  • MARCH5 mediates MAVS ubiquitination and proteasomal degradation, reducing aggregate levels.

Conclusions:

  • MARCH5 negatively regulates MAVS-mediated antiviral signalling by promoting aggregate degradation.
  • MARCH5 acts as a critical checkpoint to prevent excessive immune reactions and host immunopathology.
  • Targeting MARCH5 could offer therapeutic strategies for viral infections and inflammatory diseases.

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