Absence of DICER in Monocytes and Its Regulation by HIV-1

William Coley; Rachel Van Duyne; Lawrence Carpio; Irene Guendel; Kylene Kehn-Hall; Sebastien Chevalier; Aarthi Narayanan; Truong Luu; Norman Lee; Zachary Klase; Fatah Kashanchi

doi:10.1074/jbc.M110.101709

Absence of DICER in Monocytes and Its Regulation by HIV-1*

From the ^‡National Center for Biodefense and Infectious Diseases, Department of Molecular and Microbiology, George Mason University, Manassas, Virginia 20110,
^‖NIAID and
the ^§Laboratory of Cellular Oncology, NCI, National Institutes of Health, Bethesda, Maryland 20892, and
the ^¶Department of Pharmacology and Physiology, George Washington University School of Medicine, Washington, D. C. 20037

1 To whom correspondence should be addressed: National Center for Biodefense and Infectious Diseases, Professor of Microbiology, George Mason University, Discovery Hall, Rm. 306, 10900 University Blvd., MS 1H8, Manassas, VA 20110. Tel.: 703-993-9160; E-mail: fkashanc{at}gmu.edu.

Abstract

MicroRNAs (miRNAs) are a class of small RNA molecules that function to control gene expression and restrict viral replication in host cells. The production of miRNAs is believed to be dependent upon the DICER enzyme. Available evidence suggests that in T lymphocytes, HIV-1 can both suppress and co-opt the host's miRNA pathway for its own benefit. In this study, we examined the state of miRNA production in monocytes and macrophages as well as the consequences of viral infection upon the production of miRNA. Monocytes in general express low amounts of miRNA-related proteins, and DICER in particular could not be detected until after monocytes were differentiated into macrophages. In the case where HIV-1 was present prior to differentiation, the expression of DICER was suppressed. MicroRNA chip results for RNA isolated from transfected and treated cells indicated that a drop in miRNA production coincided with DICER protein suppression in macrophages. We found that the expression of DICER in monocytes is restricted by miR-106a, but HIV-1 suppressed DICER expression via the viral gene Vpr. Additionally, analysis of miRNA expression in monocytes and macrophages revealed evidence that some miRNAs can be processed by both DICER and PIWIL4. Results presented here have implications for both the pathology of viral infections in macrophages and the biogenesis of miRNAs. First, HIV-1 suppresses the expression and function of DICER in macrophages via a previously unknown mechanism. Second, the presence of miRNAs in monocytes lacking DICER indicates that some miRNAs can be generated by proteins other than DICER.