A First-in-Class NAE Inhibitor, MLN4924, Blocks Lentiviral Infection in Myeloid Cells by Disrupting Neddylation-Dependent Vpx-Mediated SAMHD1 Degradation

Wei, Wei; Guo, Hao; Liu, Xianjun; Zhang, Hong; Liu, Qian; Luo, Kun; Markham, Richard B.; Yu, Xiaofang

doi:10.1128/jvi.02568-13

Cited by 30 publications

(30 citation statements)

References 35 publications

(49 reference statements)

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“…MLN4924 suppresses AKT and mTOR signaling via upregulation of REDD1 in human myeloma cells (32). MLN4924 inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks macaque SIV replication in myeloid cells (17). Multiple chemical inhibitors could exert their functions with atypical mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In macrophages and dendritic cells, MLN4924 could prevent IkBa degradation, increase phosphorylated IkBa, and then repress TLR4-induced proinflammatory cytokine (TNF-a and IL-6) expression (15,16). MLN4924 blocks lentiviral infection in myeloid cells by disrupting neddylation-dependent Vpx-mediated SAMHD1 degradation, indicating the potential efficacy of inhibiting neddylation as an antiretroviral strategy (17). MLN4924 inhibits the NEDD8 cascade, blocks the action of Vif, and thus has potent anti-HIV Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China activity (18).…”

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confidence: 99%

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MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

Song

Huai

et al. 2016

The Journal of Immunology

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Neddylation is a posttranslational protein modification that conjugates ubiquitin-like protein neural precursor cell–expressed developmentally downregulated protein 8 (NEDD8) to target proteins and regulates diverse cellular processes. MLN4924, a novel NEDD8 activating enzyme inhibitor, which has emerged as a promising anticancer drug, has a multifaceted function by inhibiting the process of neddylation. However, the potential roles of MLN4924 and neddylation in IFN-β production remain unknown. In this study, we show that MLN4924 inhibits TLR3/4- and retinoic acid–inducible gene-I–induced IFN-β expression in different cells, whereas NEDD8 knockdown had no effects on IFN-β expression. The ability of the MLN4924 to inhibit IFN-β production was confirmed in vivo, as mice treated with MLN4924 exhibited decreased levels of IFN-β upon LPS or polyinosinic-polycytidylic acid stimulation. Furthermore, we show that MLN4924 inhibits IFN regulatory factor 3 (IRF3) transcriptional activation and prevents IRF3 binding to IFN-β promoter. Our findings suggest that MLN4924 inhibits TLR3/4- and retinoic acid–inducible gene-I–induced IFN-β expression by preventing IRF3 binding to the IFN-β promoter, with a neddylation-independent manner. Therefore, our results provide new insight into the mechanism of MLN4924 and may have significant implications for the treatment of MLN4924.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

Song

Huai

et al. 2016

The Journal of Immunology

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“…We and other groups have recently demonstrated that the posttranslational modification process of neddylation, which is a determinant for the activation of Cullin-RING E3 ligases, is essential for the activity of the Vpx-CRL4 (DCAF1) E3 ligase (59)(60)(61). The neddylation inhibitor MLN4924 blocks Vpx function and preserves the antiviral activity of SAMHD1.…”

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

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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-

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“…We have previously shown this higher-molecularweight band to be the neddylated form of CUL4 (91). Neddylation is required to activate cullin ubiquitin ligases and is also necessary for Vpr and Vpx functions through CRL4 (91,94,95). To test whether the single, slower-migrating band detected in the nucleus is indeed neddylated CUL4, we treated HEK293T cells with the neddylation inhibitor MLN4924 before subcellular fractionation.…”

Section: Resultsmentioning

confidence: 99%

Cullin4A and Cullin4B Are Interchangeable for HIV Vpr and Vpx Action through the CRL4 Ubiquitin Ligase Complex

Sharifi

Furuya

Jellinger

et al. 2014

J Virol

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IMPORTANCEThe work presented here shows for the first time that HIV Vpr and Vpx do not rely exclusively on CUL4A to cause ubiquitination through the CRL4 ubiquitin ligase complex. Furthermore, our finding that intracellular CUL4 and SAMHD1 distributions can vary with cell type provides the basis for reconciling previous disparate findings regarding the site of SAMHD1 depletion. Finally, our observations with primary immune cells provide insight into the cell biology of CUL4A and CUL4B that will help differentiate the functions of these similar proteins.

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A First-in-Class NAE Inhibitor, MLN4924, Blocks Lentiviral Infection in Myeloid Cells by Disrupting Neddylation-Dependent Vpx-Mediated SAMHD1 Degradation

Cited by 30 publications

References 35 publications

MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

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

Cullin4A and Cullin4B Are Interchangeable for HIV Vpr and Vpx Action through the CRL4 Ubiquitin Ligase Complex

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