Apobec3H subcellular localization determinants define zipcode for targeting HIV-1 for restriction

Daniel J. Salamango, Jordan T. Becker, Jennifer L. McCann, Adam Z. Cheng, Özlem Demir, Rommie E. Amaro, William L. Brown, Nadine M. Shaban, Reuben S. Harrisa

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

APOBEC enzymes are DNA cytosine deaminases that normally serve as virus restriction factors, but several members, including APOBEC3H, also contribute to cancer mutagenesis. Despite their importance in multiple fields, little is known about cellular processes that regulate these DNA mutating enzymes. We show that APOBEC3H exists in two distinct subcellular compartments, cytoplasm and nucleolus, and that the structural determinants for each mechanism are genetically separable. First, native and fluorescently tagged APOBEC3Hs localize to these two compartments in multiple cell types. Second, a series of genetic, pharmacologic, and cell biological studies demonstrate active cytoplasmic and nucleolar retention mechanisms, whereas nuclear import and export occur through passive diffusion. Third, APOBEC3H cytoplasmic retention determinants relocalize APOBEC3A from a passive cell-wide state to the cytosol and, additionally, endow potent HIV-1 restriction activity. These results indicate that APOBEC3H has a structural zipcode for subcellular localization and selecting viral substrates for restriction.

Original languageEnglish (US)
Article numbere00356
JournalMolecular and cellular biology
Volume38
Issue number23
DOIs
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
D.J.S. received salary support from the University of Minnesota Craniofacial Research Training (MinnCResT) program (NIH T90DE022732). N.M.S. received salary support from NIGMS R01 (GM118000). This work was supported by NIAID R37 AI064046. 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:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords

  • APOBEC3H
  • Cancer mutagenesis
  • Cytoplasmic retention
  • DNA deamination
  • Nuclear import
  • Retrovirus restriction
  • Subcellular localization

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