Biophysical Characterization of Nucleophosmin Interactions with Human Immunodeficiency Virus Rev and Herpes Simplex Virus US11

Kazem Nouri; Jens M Moll; Lech-Gustav Milroy; Anika Hain; Radovan Dvorsky; Ehsan Amin; Michael Lenders; Luitgard Nagel-Steger; Sebastian Howe; Sander H J Smits; Hartmut Hengel; Lutz Schmitt; Carsten Münk; Luc Brunsveld; Mohammad R Ahmadian

doi:10.1371/journal.pone.0143634

Biophysical Characterization of Nucleophosmin Interactions with Human Immunodeficiency Virus Rev and Herpes Simplex Virus US11

PLoS One. 2015 Dec 1;10(12):e0143634. doi: 10.1371/journal.pone.0143634. eCollection 2015.

Authors

Kazem Nouri¹, Jens M Moll¹, Lech-Gustav Milroy², Anika Hain³, Radovan Dvorsky¹, Ehsan Amin¹, Michael Lenders⁴, Luitgard Nagel-Steger^{5

6}, Sebastian Howe⁷, Sander H J Smits⁴, Hartmut Hengel^{7

8}, Lutz Schmitt⁴, Carsten Münk³, Luc Brunsveld², Mohammad R Ahmadian¹

Affiliations

¹ Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
² Laboratory of Chemical Biology & Institute of Complex Molecular Systems, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Eindhoven, Netherlands.
³ Clinic for Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
⁴ Institute of Biochemistry, Heinrich-Heine University, Düsseldorf, Germany.
⁵ Institute of Complex Systems (ICS-6), Research Centre Jülich, Jülich, Germany.
⁶ Institute of Physical Biology, Heinrich-Heine University, Düsseldorf, Germany.
⁷ Institute of Virology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
⁸ Institute of Virology, University Medical Center Freiburg, Freiburg, Germany.

Abstract

Nucleophosmin (NPM1, also known as B23, numatrin or NO38) is a pentameric RNA-binding protein with RNA and protein chaperon functions. NPM1 has increasingly emerged as a potential cellular factor that directly associates with viral proteins; however, the significance of these interactions in each case is still not clear. In this study, we have investigated the physical interaction of NPM1 with both human immunodeficiency virus type 1 (HIV-1) Rev and Herpes Simplex virus type 1 (HSV-1) US11, two functionally homologous proteins. Both viral proteins show, in mechanistically different modes, high affinity for a binding site on the N-terminal oligomerization domain of NPM1. Rev, additionally, exhibits low-affinity for the central histone-binding domain of NPM1. We also showed that the proapoptotic cyclic peptide CIGB-300 specifically binds to NPM1 oligomerization domain and blocks its association with Rev and US11. Moreover, HIV-1 virus production was significantly reduced in the cells treated with CIGB-300. Results of this study suggest that targeting NPM1 may represent a useful approach for antiviral intervention.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biophysical Phenomena*
COS Cells
Chlorocebus aethiops
HIV-1
HeLa Cells
Humans
Models, Molecular
Nuclear Proteins / chemistry
Nuclear Proteins / metabolism*
Nucleophosmin
Peptides, Cyclic / metabolism
Protein Binding
Protein Multimerization
Protein Structure, Quaternary
RNA-Binding Proteins / chemistry
RNA-Binding Proteins / metabolism*
Viral Proteins / chemistry
Viral Proteins / metabolism*
rev Gene Products, Human Immunodeficiency Virus / chemistry
rev Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

NPM1 protein, human
Nuclear Proteins
Peptides, Cyclic
RNA-Binding Proteins
US11 protein, herpesvirus
Viral Proteins
rev Gene Products, Human Immunodeficiency Virus
rev protein, Human Immunodeficiency Virus-1
Nucleophosmin
CIGB-300

Grants and funding

This work was funded by the International Graduate School of Protein Science and Technology (iGRASP), Research Commission of the Medical Faculty and the Strategic Research Fund (SFF) of Heinrich-Heine University Düsseldorf, and the German Research Foundation (Deutsche Forschungsgemeinschaft or DFG) through the Collaborative Research Center 974 (SFB 974) “Communication and Systems Relevance during Liver Injury and Regeneration”, the International Research Training Group 1902 (IRTG 1902) “Intra- and interorgan communication of the cardiovascular system”, and GRK 1045 “Modulation of host cell function”. CM is supported by the Heinz Ansmann foundation. AH is supported by the Jürgen Manchot Foundation, Molecules of Infection Graduate School.