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 language | English (US) |
|---|---|
| Pages (from-to) | 1-15 |
| Number of pages | 15 |
| Journal | Translational Research |
| Volume | 237 |
| DOIs | |
| State | Published - Nov 2021 |
Funding
Conflicts of Interest: The authors have read the journal's policy on disclosure of potential conflicts of interest and declare no competing interests. Funding: This work was supported by P01 AI 131346 (G.K.S. I.C. C.S. R.T.D.), a supplement to the Robert H. Lurie Comprehensive Cancer Center (P30 CA 060553-24S3) (C.S.), the U.S. Army Medical Research and Material Command (W81XWH-15-1-0105) (M.R.), a Chicago Baseball Charities Cancer Charities Award (G.K.S.), the Sidney Kohl Family Foundation (R.T.D.) and the Northwestern Medicine Catalyst Fund (R.T.D.). We also acknowledge core resources, a Developmental Core pilot project award (C.S.), and consultations from the Third Coast Center for AIDS Research (CFAR), an NIH funded center (P30 AI117943). Author contributions are as follow: G.K.S. C.S. M.R. and R.T.D. conceived the hypothesis. G.K.S. A.M.S. C.C.V. I.C. M.R. and C.S. performed the experiments. G.K.S. A.M.S. C.C.V. I.C. M.R. C.S. and R.T.D. designed and interpreted the results. G.K.S. C.S. and R.T.D. wrote the manuscript. All authors confirm that they have reviewed and approved the journal's authorship agreement. We thank Hannah Hudson, Nina Calantone, and Harry E. Taylor for their continued support and feedback throughout the course of these experiments. We would additionally like to thank Dr Goo and the Northwestern University Proteomics Core. Funding: This work was supported by P01 AI 131346 (G.K.S., I.C., C.S., R.T.D.), a supplement to the Robert H. Lurie Comprehensive Cancer Center (P30 CA 060553-24S3 ) (C.S.), the U.S. Army Medical Research and Material Command ( W81XWH-15-1-0105 ) (M.R.), a Chicago Baseball Charities Cancer Charities Award (G.K.S.), the Sidney Kohl Family Foundation (R.T.D.) and the Northwestern Medicine Catalyst Fund (R.T.D.). We also acknowledge core resources, a Developmental Core pilot project award (C.S.), and consultations from the Third Coast Center for AIDS Research (CFAR), an NIH funded center (P30 AI117943 ).
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
