APOBEC3H Subcellular Localization Determinants Define Zipcode for Targeting HIV-1 for Restriction

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2018 Sep 19

PMID 30224517

Citations 12

Authors

Daniel J Salamango

Jordan T Becker

Jennifer L McCann

Adam Z Cheng

Ozlem Demir

Rommie E Amaro

William L Brown

Nadine M Shaban

Reuben S Harris

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Lange A, Mills R, Lange C, Stewart M, Devine S, Corbett A . Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2006; 282(8):5101-5. PMC: 4502416. DOI: 10.1074/jbc.R600026200. View

Martin R, Ter-Avetisyan G, Herce H, Ludwig A, Lattig-Tunnemann G, Cardoso M . Principles of protein targeting to the nucleolus. Nucleus. 2015; 6(4):314-25. PMC: 4615656. DOI: 10.1080/19491034.2015.1079680. View

Phalora P, Sherer N, Wolinsky S, Swanson C, Malim M . HIV-1 replication and APOBEC3 antiviral activity are not regulated by P bodies. J Virol. 2012; 86(21):11712-24. PMC: 3486339. DOI: 10.1128/JVI.00595-12. View

Sun Q, Carrasco Y, Hu Y, Guo X, Mirzaei H, MacMillan J . Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Proc Natl Acad Sci U S A. 2013; 110(4):1303-8. PMC: 3557022. DOI: 10.1073/pnas.1217203110. View

Burns M, Lackey L, Carpenter M, Rathore A, Land A, Leonard B . APOBEC3B is an enzymatic source of mutation in breast cancer. Nature. 2013; 494(7437):366-70. PMC: 3907282. DOI: 10.1038/nature11881. View

Teng B, Burant C, Davidson N . Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science. 1993; 260(5115):1816-9. DOI: 10.1126/science.8511591. View

Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P . Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science. 2003; 302(5647):1056-60. DOI: 10.1126/science.1089591. View

Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria J . Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis. PLoS Med. 2016; 13(12):e1002201. PMC: 5189935. DOI: 10.1371/journal.pmed.1002201. View

Lackey L, Law E, Brown W, Harris R . Subcellular localization of the APOBEC3 proteins during mitosis and implications for genomic DNA deamination. Cell Cycle. 2013; 12(5):762-72. PMC: 3610724. DOI: 10.4161/cc.23713. View

10.

Muckenfuss H, Hamdorf M, Held U, Perkovic M, Lower J, Cichutek K . APOBEC3 proteins inhibit human LINE-1 retrotransposition. J Biol Chem. 2006; 281(31):22161-22172. DOI: 10.1074/jbc.M601716200. View

11.

LaRue R, Jonsson S, Silverstein K, Lajoie M, Bertrand D, El-Mabrouk N . The artiodactyl APOBEC3 innate immune repertoire shows evidence for a multi-functional domain organization that existed in the ancestor of placental mammals. BMC Mol Biol. 2008; 9:104. PMC: 2612020. DOI: 10.1186/1471-2199-9-104. View

12.

SCHOEFL G . THE EFFECT OF ACTINOMYCIN D ON THE FINE STRUCTURE OF THE NUCLEOLUS. J Ultrastruct Res. 1964; 10:224-43. DOI: 10.1016/s0022-5320(64)80007-1. View

13.

Szekely L, Jiang W, Pokrovskaja K, Wiman K, Klein G, RINGERTZ N . Reversible nucleolar translocation of Epstein-Barr virus-encoded EBNA-5 and hsp70 proteins after exposure to heat shock or cell density congestion. J Gen Virol. 1995; 76 ( Pt 10):2423-32. DOI: 10.1099/0022-1317-76-10-2423. View

14.

York A, Kutluay S, Errando M, Bieniasz P . The RNA Binding Specificity of Human APOBEC3 Proteins Resembles That of HIV-1 Nucleocapsid. PLoS Pathog. 2016; 12(8):e1005833. PMC: 4991800. DOI: 10.1371/journal.ppat.1005833. View

15.

Bohn M, Shandilya S, Silvas T, Nalivaika E, Kouno T, Kelch B . The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization. Structure. 2015; 23(5):903-911. PMC: 4874493. DOI: 10.1016/j.str.2015.03.016. View

16.

RECHER L, Briggs L, Parry N . A reevaluation of nuclear and nucleolar changes induced in vitro by actinomycin D. Cancer Res. 1971; 31(2):140-51. View

17.

Grummt I, Langst G . Epigenetic control of RNA polymerase I transcription in mammalian cells. Biochim Biophys Acta. 2012; 1829(3-4):393-404. DOI: 10.1016/j.bbagrm.2012.10.004. View

18.

Li M, Emerman M . Polymorphism in human APOBEC3H affects a phenotype dominant for subcellular localization and antiviral activity. J Virol. 2011; 85(16):8197-207. PMC: 3147987. DOI: 10.1128/JVI.00624-11. View

19.

Wang T, Zhang W, Tian C, Liu B, Yu Y, Ding L . Distinct viral determinants for the packaging of human cytidine deaminases APOBEC3G and APOBEC3C. Virology. 2008; 377(1):71-9. PMC: 2692739. DOI: 10.1016/j.virol.2008.04.012. View

20.

Salamango D, McCann J, Demir O, Brown W, Amaro R, Harris R . APOBEC3B Nuclear Localization Requires Two Distinct N-Terminal Domain Surfaces. J Mol Biol. 2018; 430(17):2695-2708. PMC: 6456046. DOI: 10.1016/j.jmb.2018.04.044. View