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

Ruth Hüttenhain*, Jiewei Xu, Lily A. Burton, David E. Gordon, Judd F. Hultquist, Jeffrey R. Johnson, L. Satkamp, Joseph Hiatt, David Y. Rhee, Kheewoong Baek, David C. Crosby, Alan D. Frankel, Alexander Marson, J. Wade Harper, Arno F. Alpi, Brenda A. Schulman, John D. Gross, Nevan J. Krogan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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. Degradation of APOBEC3 proteins by HIV Vif hijacking Cullin RING E3 ligase 5 is essential for HIV proliferation. Hüttenhain et al. discovered the host factor ARIH2, which works with CUL5Vif/CBFß via a tag-team mechanism to target APOBEC3 proteins for ubiquitination and is essential for HIV proliferation in primary CD4+ T cells.

Original languageEnglish (US)
Pages (from-to)86-99.e7
JournalCell Host and Microbe
Issue number1
StatePublished - Jul 10 2019


  • AP-MS
  • ARIH2
  • CUL5
  • HIV
  • Vif
  • host-virus interactions

ASJC Scopus subject areas

  • Virology
  • Parasitology
  • Microbiology


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