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

• Published in: Translational research : the journal of laboratory and clinical medicine 2021-11, Vol.237, p.1-15
• Main Authors: Scholtés, Gaël K., Sawyer, Aubrey M., Vaca, Cristina C., Clerc, Isabelle, Roh, Meejeon, Song, Chisu, D'Aquila, Richard T.
• Format: Article
• Language: English
• Subjects: APOBEC Deaminases - genetics; APOBEC Deaminases - metabolism; ariadne RING-in-between-RING E3 ubiquitin ligase; Cell Line, Tumor; Cullin-RING E3 ubiquitin ligase; Down-Regulation; Gene Expression Regulation, Enzymologic - physiology; human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3; human immunodeficiency virus; Humans; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; virion infectivity factor; von Hippel-Lindau protein
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2021.05.002

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.