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CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus

Madina Mahesutihan1,2, Weinan Zheng1, Liang Cui1,2

  • 1CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.

Virologica Sinica
|October 18, 2018
PubMed

Insights

Cyclophilin A (CypA) restricts influenza A virus (IAV) replication by inhibiting the ubiquitination of the M1 protein. This novel mechanism involves CypA blocking the E3 ligase AIP4, preventing M1 degradation and controlling viral spread.

Area of Science:

  • Virology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclophilin A (CypA) is known to interact with influenza A virus (IAV) matrix protein (M1) and restrict viral replication.
  • The precise mechanism by which CypA influences M1 ubiquitination and subsequent degradation remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which CypA regulates M1 ubiquitination and its impact on IAV replication.
  • To identify the specific E3 ubiquitin ligase involved in M1 ubiquitination and explore CypA's inhibitory role.

Main Methods:

  • Investigated the role of E3 ubiquitin ligase AIP4 in M1 ubiquitination using in vitro and in vivo assays.
  • Utilized site-directed mutagenesis to create IAV with M1 mutations (K102R/K104R) to assess the importance of ubiquitination sites.
  • Examined the interaction between CypA, AIP4, and M1 using co-immunoprecipitation assays.
  • Assessed the effect of M1 mutations and CypA on M1 cellular localization and IAV replication.

Main Results:

  • E3 ubiquitin ligase AIP4 was found to promote K48-linked ubiquitination of M1 at lysine residues K102 and K104, accelerating M1 degradation.
  • Recombinant IAV with M1 mutations at K102/K104 could not be rescued, indicating these ubiquitination sites are essential for viral replication.
  • CypA inhibited AIP4-mediated M1 ubiquitination by disrupting the AIP4-M1 interaction.
  • Both M1 mutations (K102R/K104R) and CypA treatment inhibited M1 nuclear export, leading to reduced IAV replication.

Conclusions:

  • CypA regulates IAV replication through a novel ubiquitination-dependent pathway.
  • CypA inhibits M1 ubiquitination by targeting the AIP4-M1 interaction, thereby preventing M1 degradation and controlling viral nuclear export and replication.
Keywords:
AIP4Cyclophilin A (CypA)Influenza A virus (IAV)M1Ubiquitination

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