Cyclin L2 Is a Critical HIV Dependency Factor in Macrophages that Controls SAMHD1 Abundance

Kyei, George B.; Cheng, Xiaogang; Ramani, Rashmi; Ratner, Lee

doi:10.1016/j.chom.2014.11.009

Cited by 45 publications

(44 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phosphorylated forms of SAMHD1 may be associated in cell culture with an unidentified repressor that controls SAMHD1 function. This latter hypothesis is supported by the observation that cyclin L2, an RNA polymerase II-associated cyclin [34], forms a complex with DCAF1 and SAMHD1 [52], targeting it for proteasomal degradation. Alternatively, how the phosphohydrolase activity affects the antiviral activity of SAMHD1 should be revisited.…”

Section: Rnasementioning

confidence: 89%

SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

Ballana

Esté

2015

Trends in Microbiology

View full text Add to dashboard Cite

Section: Rnasementioning

confidence: 89%

SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

Ballana

Esté

2015

Trends in Microbiology

View full text Add to dashboard Cite

“…Vpx is a virionassociated viral accessory protein present in HIV-2 and selected SIV lineages (15,18). Although Vpx has only a moderate effect on viral replication in CD4 ϩ T lymphocytes, with some degree of individual variation (10,(24)(25)(26), it is essential for efficient viral replication in macrophages (10,27) and dendritic cells (28,29). In SIV-infected monkeys, Vpx is required for viral dissemination and disease progression (30,31).…”

Section: Importancementioning

confidence: 99%

Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly

Wang

Guo

et al. 2017

J Virol

View full text Add to dashboard Cite

The lentiviral accessory proteins Vpx and Vpr are known to utilize CRL4 (DCAF1) E3 ligase to induce the degradation of the host restriction factor SAMHD1 or host helicase transcription factor (HLTF), respectively. Selective disruption of viral CRL4 (DCAF1) E3 ligase could be a promising antiviral strategy. Recently, we have determined that posttranslational modification (neddylation) of Cullin-4 is required for the activation of Vpx-CRL4 (DCAF1) E3 ligase. However, the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly is still poorly understood. Here, we report that zinc coordination is an important regulator of Vpx-CRL4 E3 ligase assembly. Residues in a conserved zinc-binding motif of Vpx were essential for the recruitment of the CRL4 (DCAF1) E3 complex and Vpx-induced SAMHD1 degradation. Importantly, altering the intracellular zinc concentration by treatment with the zinc chelator N,N,N=-tetrakis-(2=-pyridylmethyl)ethylenediamine (TPEN) potently blocked Vpx-mediated SAMHD1 degradation and inhibited wild-type SIVmac (simian immunodeficiency virus of macaques) infection of myeloid cells, even in the presence of Vpx. TPEN selectively inhibited Vpx and DCAF1 binding but not the Vpx-SAMHD1 interaction or Vpx virion packaging. Moreover, we have shown that zinc coordination is also important for the assembly of the HIV-1 Vpr-CRL4 E3 ligase. In particular, Vpr zinc-binding motif mutation or TPEN treatment efficiently inhibited Vpr-CRL4 (DCAF1) E3 ligase assembly and Vpr-mediated HLTF degradation or Vpr-induced G 2 cell cycle arrest. Collectively, our study sheds light on a conserved strategy by the viral proteins Vpx and Vpr to recruit host CRL4 (DCAF1) E3 ligase, which represents a target for novel antihuman immunodeficiency virus (HIV) drug development.IMPORTANCE The Vpr and its paralog Vpx are accessory proteins encoded by different human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) lentiviruses. To facilitate viral replication, Vpx has evolved to induce SAMHD1 degradation and Vpr to mediate HLTF degradation. Both Vpx and Vpr perform their functions by recruiting CRL4 (DCAF1) E3 ligase. In this study, we demonstrate that the assembly of the Vpx-or Vpr-CRL4 E3 ligase requires a highly conserved zinc-binding motif. This motif is specifically required for the DCAF1 interaction but not for the interaction of Vpx or Vpr with its substrate. Selective disruption of Vpx-or Vpr-CRL4 E3 ligase function was achieved by zinc sequestration using N,N,N=-tetrakis-(2=-pyridylmethyl) ethylenediamine (TPEN). At the same time, zinc sequestration had no effect on zinc-

show abstract

“…33 Thus, cyclin L2 controls the abundance of SAMHD1 as an alternative mechanism regulating SAMHD1-mediated restriction. We have not observed differences in total SAMHD1 mRNA expression between HIV-1 restricted and susceptible macrophages 34 and SAMHD1 is ubiquitously expressed in monocytes, MDM, and in resting and activated CD4C T cells.…”

Section: 18mentioning

confidence: 99%

Cyclin D3-dependent control of the dNTP pool and HIV-1 replication in human macrophages

et al. 2015

View full text Add to dashboard Cite

Cyclins control the activation of cyclin-dependent kinases (CDK), which in turn, control the cell cycle and cell division. Intracellular availability of deoxynucleotides (dNTP) plays a fundamental role in cell cycle progression. SAM domain and HD domain-containing protein 1 (SAMHD1) degrades nucleotide triphosphates and controls the size of the dNTP pool. SAMHD1 activity appears to be controlled by CDK. Here, we show that knockdown of cyclin D3 a partner of CDK6 and E2 a partner of CDK2 had a major impact in SAMHD1 phosphorylation and inactivation and led to decreased dNTP levels and inhibition of HIV-1 at the reverse transcription step in primary human macrophages. The effect of cyclin D3 RNA interference was lost after degradation of SAMHD1 by HIV-2 Vpx, demonstrating the specificity of the mechanism. Cyclin D3 inhibition correlated with decreased activation of CDK2. Our results confirm the fundamental role of the CDK6-cyclin D3 pair in controlling CDK2-dependent SAMHD1 phosphorylation and dNTP pool in primary macrophages.

show abstract

Cyclin L2 Is a Critical HIV Dependency Factor in Macrophages that Controls SAMHD1 Abundance

Cited by 45 publications

References 36 publications

SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly

Cyclin D3-dependent control of the dNTP pool and HIV-1 replication in human macrophages

Contact Info

Product

Resources

About