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 journalArticlepeer-review

14 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

Bibliographical note

Funding Information:
This work was supported by NIAID R37 AI064046 (to R.S.H.) and a Collaborative Development Project sub-award from NIGMS 2U54GM103368 and NIAID R21 AI138793 (to D.E.). D.J.S. received salary support from the University of Minnesota Craniofacial Research Training (MinnCResT) program (NIH T90 DE022732) and from a NIAID K99/R00 career transition award (K99 AI147811). R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute. D.J.S. and R.S.H. led the project. D.J.S. made all DNA constructs and performed most of the experiments. J.L.M. contributed immunoblots, A.A.S. and S.A.M. to knockdown studies, T.I. and J.W. to cell-based studies, D.E. and M.C.J. to sequence comparisons, and W.L.B. to project logistics. D.J.S. and R.S.H. drafted the manuscript, and all authors contributed to revisions. R.S.H. is a co-founder, shareholder, and consultant of ApoGen Biotechnologies Inc.

Funding Information:
This work was supported by NIAID R37 AI064046 (to R.S.H.) and a Collaborative Development Project sub-award from NIGMS 2U54GM103368 and NIAID R21 AI138793 (to D.E.). D.J.S. received salary support from the University of Minnesota Craniofacial Research Training (MinnCResT) program ( NIH T90 DE022732 ) and from a NIAID K99/R00 career transition award ( K99 AI147811 ). R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2019 The Author(s)

Keywords

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

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