The Dual-Specificity Kinase DYRK1A Modulates the Levels of Cyclin L2 To Control HIV Replication in Macrophages

Abstract

HIV replication in macrophages contributes to the latent viral reservoirs, which are 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. Mutations 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 antiretroviral therapy (ART) can control the virus, it does not provide cure. The virus hides in the genomes of long-lived cells, such as 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.

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

“…Tendinopathy [195] DYRK1A Human immunodeficiency virus type 1 (HIV-1) [196][197][198] DYRK1A DYRK1B Human cytomegalovirus (HCMV) [199] DYRK1B…”

Interplay Between CMGC Kinases Targeting SR Proteins and Viral Replication: Splicing and Beyond

“…First, even if in most cases the mechanisms, underlying the pro- or antiviral activity of these kinases, were not uncovered, available data indicate that they exert their effects at multiple steps of viral life cycles ( Figure 5 ). SRPK1 and DYRK1A can control the transcription of EBOV and HIV RNAs by phosphorylating viral and cellular factors ( Booiman et al, 2015 ; Kisaka et al, 2020 ; Takamatsu et al, 2020 ). In the case of DYRK1A, this activity may also extend to other viruses thanks to its intrinsic capacity to phosphorylate the host RNA polymerase II CTD and modulate its activity.…”

“…Even if the consequences of this polymorphism on the enzyme were not investigated, subsequent studies showed that DYRK1A can downregulate HIV-1 transcription likely by phosphorylating NFAT, a transcription factor of the HIV-1 LTR, and by inducing its translocation into the cytoplasm ( Booiman et al, 2015 ). Further studies also pointed to a role of DYRK1A in the inhibition of HIV-1 replication in macrophages by phosphorylating Cyclin L2 and inducing its degradation ( Kisaka et al, 2020 ). The antiviral effect of DYRK1A was shown to occur at the transcriptional level.…”

Human sialomucin CD164 is an essential entry factor for lymphocytic choriomeningitis virus

“…The LCMV attachment factor DAG1 was detected, albeit at a lower enrichment score. Additional host factors that were significantly enriched include those described for other viral infections, such as negative-stranded RNA virus vesicular stomatitis virus (VSV) (ARFRP1, SYS1, YKT6) and the human immunodeficiency virus (HIV) (SRP14, DYRK1A, IL2RA) (33)(34)(35)(36)(37).…”