ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection

Cell Host Microbe. 2019 Jul 10;26(1):86-99.e7. doi: 10.1016/j.chom.2019.05.008. Epub 2019 Jun 25.


The Cullin-RING E3 ligase (CRL) family is commonly hijacked by pathogens to redirect the host ubiquitin proteasome machinery to specific targets. During HIV infection, CRL5 is hijacked by HIV Vif to target viral restriction factors of the APOBEC3 family for ubiquitination and degradation. Here, using a quantitative proteomics approach, we identify the E3 ligase ARIH2 as a regulator of CRL5-mediated APOBEC3 degradation. The CUL5Vif/CBFß complex recruits ARIH2 where it acts to transfer ubiquitin directly to the APOBEC3 targets. ARIH2 is essential for CRL5-dependent HIV infectivity in primary CD4+ T cells. Furthermore, we show that ARIH2 cooperates with CRL5 to prime other cellular substrates for polyubiquitination, suggesting this may represent a general mechanism beyond HIV infection and APOBEC3 degradation. Taken together, these data identify ARIH2 as a co-factor in the Vif-hijacked CRL5 complex that contributes to HIV infectivity and demonstrate the operation of the E1-E2-E3/E3-substrate ubiquitination mechanism in a viral infection context.

Keywords: AP-MS; APOBEC3; ARIH2; CUL5; HIV; Vif; host-virus interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC-3G Deaminase / metabolism*
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Cullin Proteins / metabolism*
  • HIV Infections / pathology*
  • Host-Pathogen Interactions*
  • Humans
  • Immune Evasion*
  • Models, Theoretical
  • Proteolysis
  • Proteome / analysis
  • Ubiquitin-Protein Ligases / metabolism*
  • Virus Replication
  • vif Gene Products, Human Immunodeficiency Virus / metabolism*


  • CUL5 protein, human
  • Cullin Proteins
  • Proteome
  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • ARIH2 protein, human
  • Ubiquitin-Protein Ligases
  • APOBEC-3G Deaminase