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; Laura 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

doi:10.1016/j.chom.2019.05.008

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.

Authors

Ruth Hüttenhain¹, Jiewei Xu², Lily A Burton³, David E Gordon², Judd F Hultquist⁴, Jeffrey R Johnson², Laura Satkamp², Joseph Hiatt⁵, David Y Rhee⁶, Kheewoong Baek⁷, David C Crosby⁸, Alan D Frankel⁸, Alexander Marson⁹, J Wade Harper⁶, Arno F Alpi⁷, Brenda A Schulman⁷, John D Gross³, Nevan J Krogan¹⁰

Affiliations

¹ Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), San Francisco, CA 94158, USA. Electronic address: ruth.huttenhain@ucsf.edu.
² Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), San Francisco, CA 94158, USA.
³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), San Francisco, CA 94158, USA; Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁵ Gladstone Institutes, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
⁸ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), San Francisco, CA 94158, USA. Electronic address: nevan.krogan@ucsf.edu.

Abstract

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 CUL5^Vif/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*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding