The von Hippel–Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases

Gael K. Scholtes, Aubrey M. Sawyer, Cristina C. Vaca, Isabelle Clerc, Meejeon Roh, Chisu Song*, Richard T. D'Aquila

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The 7 members of the A3 family of cytidine deaminases (A3A to A3H) share a conserved catalytic activity that converts cytidines in single-stranded (ss) DNA into uridines, thereby inducing mutations. After their initial identification as cell-intrinsic defenses against HIV and other retroviruses, A3s were also found to impair many additional viruses. Moreover, some of the A3 proteins (A3A, A3B, and A3H haplotype I) are dysregulated in cancer cells, thereby causing chromosomal mutations that can be selected to fuel progression of malignancy. Viral mechanisms that increase transcription of A3 genes or induce proteasomal degradation of A3 proteins have been characterized. However, only a few underlying biological mechanisms regulating levels of A3s in uninfected cells have been described. Here, we characterize that the von Hippel–Lindau tumor suppressor (pVHL), via its CRLpVHL, induces degradation of all 7 A3 proteins. Two independent lines of evidence supported the conclusion that the multiprotein CRLpVHL complex is necessary for A3 degradation. CRLpVHL more effectively induced degradation of nuclear, procancer A3 (A3B) than the cytoplasmic, antiretroviral A3 (A3G). These results identify specific cellular factors that regulate A3s post-translationally.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalTranslational Research
Volume237
DOIs
StateAccepted/In press - 2021

Keywords

  • Cullin-RING E3 ubiquitin ligase
  • ariadne RING-in-between-RING E3 ubiquitin ligase
  • human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3
  • human immunodeficiency virus
  • virion infectivity factor
  • von Hippel-Lindau protein

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Physiology (medical)
  • Biochemistry, medical

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