HIV-1 Vif Triggers Cell Cycle Arrest by Degrading Cellular PPP2R5 Phospho-regulators

Daniel J. Salamango, Terumasa Ikeda, Seyed Arad Moghadasi, Jiayi Wang, Jennifer L. McCann, Artur A. Serebrenik, Diako Ebrahimi, Matthew C. Jarvis, William L. Brown, Reuben S. Harris

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

HIV-1 Vif hijacks a cellular ubiquitin ligase complex to degrade antiviral APOBEC3 enzymes and PP2A phosphatase regulators (PPP2R5A–E). APOBEC3 counteraction is essential for viral pathogenesis. However, Vif also functions through an unknown mechanism to induce G2 cell cycle arrest. Here, deep mutagenesis is used to define the Vif surface required for PPP2R5 degradation and isolate a panel of separation-of-function mutants (PPP2R5 degradation-deficient and APOBEC3G degradation-proficient). Functional studies with Vif and PPP2R5 mutants were combined to demonstrate that PPP2R5 is, in fact, the target Vif degrades to induce G2 arrest. Pharmacologic and genetic approaches show that direct modulation of PP2A function or depletion of specific PPP2R5 proteins causes an indistinguishable arrest phenotype. Vif function in the cell cycle checkpoint is present in common HIV-1 subtypes worldwide and likely advantageous for viral pathogenesis.

Original languageEnglish (US)
Pages (from-to)1057-1065.e4
JournalCell reports
Volume29
Issue number5
DOIs
StatePublished - Oct 29 2019

Keywords

  • HIV-1
  • Vif
  • cell cycle checkpoint
  • host-pathogen interaction
  • phosphatase regulation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Salamango, D. J., Ikeda, T., Moghadasi, S. A., Wang, J., McCann, J. L., Serebrenik, A. A., Ebrahimi, D., Jarvis, M. C., Brown, W. L., & Harris, R. S. (2019). HIV-1 Vif Triggers Cell Cycle Arrest by Degrading Cellular PPP2R5 Phospho-regulators. Cell reports, 29(5), 1057-1065.e4. https://doi.org/10.1016/j.celrep.2019.09.057