Levels of the several different human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) cytidine deaminases vary across different cell types. While levels of nuclear-localized A3s are low or non-existent in primary cells, a nuclear A3 is often upregulated in cancer cells. Increased chromosomal mutagenesis due to nuclear A3 up-regulation adds genetic diversity from which more aggressive cancer cells are selected. In contrast, relatively increased cellular levels of different, related cytoplasmic A3s in certain T-lymphocyte subtypes/differentiation states are beneficially associated with a stronger defense against HIV replication. Thus, modulation of all A3 levels in the same direction may have opposite effects on pathogenesis of cancer and HIV. The underlying cellular regulatory mechanisms of A3s that could inform development of specific interventions against either cancer or retrovirus infection are not yet well characterized. We now identify post-translational regulation of A3s by the von Hippel–Lindau tumor suppressor (pVHL), which is the substrate recognition receptor of a specific Cullin (CUL)-RING E3 ubiquitin ligase complex (CRLpVHL). This parallels the well-characterized mechanism by which the retroviral VIF protein recruits A3s to a different CRL complex (CRLVIF). Notably, CRLpVHL differentially induces more effective degradation of nuclear, pro-cancer A3 than a cytoplasmic, anti-retroviral A3. Results presented here suggest opportunities to develop strategies that can limit mutagenic contributions of A3s to cancer progression while minimizing impairment of their defenses against exogenous retroviruses.

Creator

• Scholtes, Gael Kaushik

DOI

• https://doi.org/10.21985/n2-z611-xr25

Subject

• Cellular biology

Language

• en

Alternate Identifier

• etdadmin_upload_822125
• http://dissertations.umi.com/northwestern:15598

Keyword

• VHL
• HIV
• Proteasome
• APOBEC

Date created

• 2021-01-01

Resource type

• Dissertation

Rights statement

• In Copyright