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J Virol. 2019 Dec 18. pii: JVI.01583-19. doi: 10.1128/JVI.01583-19. [Epub ahead of print]

The dual specificity kinase DYRK1A modulates the levels of cyclin L2 to control HIV replication in macrophages.

Author information

1
From the Department of Medicine, Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, Missouri, 63110, USA.
2
From the Department of Medicine, Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, Missouri, 63110, USA. g.kyei@wustl.edu.
3
Department of Virology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana.

Abstract

HIV replication in macrophages contributes to the latent viral reservoirs which is considered the main barrier to HIV eradication. Few cellular factors that facilitate HIV replication in latently infected cells are known. We previously identified cyclin L2 as a critical factor required by HIV-1, and found that depletion of cyclin L2 attenuates HIV-1 replication in macrophages. Here we demonstrate that cyclin L2 promotes HIV-1 replication through interactions with the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Cyclin L2 and DYRK1A were colocalized in the nucleus and were found together in immunoprecipitation experiments. Knockdown or inhibition of DYRK1A increased HIV-1 replication in macrophages while depletion of cyclin L2 decreased HIV-1 replication. Furthermore, depletion of DYRK1A increased expression levels of cyclin L2. DYRK1A is a proline directed kinase that phosphorylates cyclin L2 at serine residues. Mutants of cyclin L2 at serine residues preceding proline significantly stabilized cyclin L2 and increased HIV-1 replication in macrophages. Thus, we propose that DYRK1A controls cyclin L2 expression leading to restriction of HIV replication in macrophages.Importance HIV continues to be a major public health problem worldwide with over 36 million people living with the virus. Although anti-retroviral therapy (ART) can control the virus, it does not provide cure. The virus hides in the genome of long-lived cells like resting CD4+ T cells and differentiated macrophages. To get a cure for HIV, it is important to identify and characterize the cellular factors that control HIV multiplication in these reservoir cells. Previous work showed that cyclin L2 is required for HIV replication in macrophages. However, how cyclin L2 is regulated in macrophages is unknown. Here, we show that the protein DYRK1A interacts with and phosphorylates cyclin L2. Phosphorylation makes cyclin L2 amenable to cellular degradation, leading to restriction of HIV replication in macrophages.

PMID:
31852782
DOI:
10.1128/JVI.01583-19
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