Understanding the molecular manipulation of DCAF1 by the lentiviral accessory proteins Vpr and Vpx

Cassiday, Patrick A; DePaula-Silva, Ana Beatriz; Chumley, Jeffrey; Ward, Jeffrey P.; Barker, Edward; Planelles, Vicente

doi:10.1016/j.virol.2014.11.024

Cited by 9 publications

(11 citation statements)

References 52 publications

(81 reference statements)

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“…Comparing with human ( Homo sapiens [ Hs ]) DCAF1, Drosophila melanogaster ( Dm ) Mahj also contains a LisH motif, a helix-loop-helix (HLH) motif, a WD40 domain, and an acidic domain (Fig 4B). The LisH motif of Hs DCAF1 is responsible for the dimerization of DCAF1 [37], whereas the HLH motif and WD40 domain are important for the binding of DCAF1 to DDB1 [38–40]. From our homology model of the Dm Mahj- Dm DDB1 complex, which was generated from the published crystal structure of the Hs DCAF1- Hs DDB1 complex (Protein Data Bank [PDB] 5JK7 [39]), Mahj likely uses its HLH motif and WD40 domain to interact with DDB1 (S4A–S4C Fig).…”

Section: Resultsmentioning

confidence: 99%

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CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation

Tan

Koe

et al. 2019

PLoS Biol

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The ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4 Mahj , an evolutionarily conserved E3 ubiquitin ligase, is essential for NSC reactivation (exit from quiescence). We demonstrate that damaged DNA-binding protein 1 (DDB1) and Cullin4, two core components of Cullin4-RING ligase (CRL4), are intrinsically required for NSC reactivation. We have identified a substrate receptor of CRL4, Mahjong (Mahj), which is necessary and sufficient for NSC reactivation. Moreover, we show that CRL4 Mahj forms a protein complex with Warts (Wts/large tumor suppressor [Lats]), a kinase of the Hippo signaling pathway, and Mahj promotes the ubiquitination of Wts. Our genetic analyses further support the conclusion that CRL4 Mahj triggers NSC reactivation by inhibition of Wts. Given that Cullin4B mutations cause mental retardation and cerebral malformation, similar regulatory mechanisms may be applied to the human brain.

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Section: Resultsmentioning

confidence: 99%

“…Besides binding to Hs DDB1, the WD40 domain of Hs DCAF1 is also critical for interaction with substrates [38,40]. Therefore, we explored whether the WD40 domain of Mahj mediated its interaction with Wts.…”

Section: Resultsmentioning

confidence: 99%

CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation

Tan

Koe

et al. 2019

PLoS Biol

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“…Vpr has two widely studied activities: one is its ability to induce G 2 cell cycle arrest, and the other is to increase HIV-1 replication in macrophages (32, 33). The molecular mechanism of G 2 arrest induction by Vpr has been attributed to a number of host target proteins (34, 35). In one report, Vpr is found to target MUS81 for degradation through the CRL4 VprBP E3 ligase, resulting in premature activation of the SLX4 complex.…”

Section: Discussionmentioning

confidence: 99%

Vpr Enhances HIV-1 Env Processing and Virion Infectivity in Macrophages by Modulating TET2-Dependent IFITM3 Expression

Wang

2019

mBio

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HIV-1 Vpr enhances viral replication in human macrophages via multiple mechanisms that are not clearly defined. It does not affect HIV-1 virion production during the first round of infection. We have recently discovered that Vpr targets the DNA demethylase TET2 for degradation, which leads to sustained interleukin-6 (IL-6) expression and elevated HIV-1 replication. We report here that Vpr enhanced Env processing in infected macrophages, associated with increased Env incorporation into virions with higher infectivity. Interestingly, IFITM3 was constitutively expressed in macrophages in a TET2-dependent fashion. We showed that Vpr-enhanced Env processing depended genetically on TET2 and IFITM3. We further showed that Vpr reduced IFITM3 expression by reducing demethylation of the IFITM3 promoter in macrophages, associated with degradation of TET2 and reduced TET2 binding to the IFITIM3 promoter. Our findings indicate that the Vpr-TET2 axis enhances HIV-1 replication in macrophages via two independent mechanisms: reduced IFTIM3 expression to enhance Env processing and virion infectivity and sustained IL-6 expression to increase HIV-1 replication. The Vpr-TET2 axis may provide a novel target to develop therapeutics to inhibit HIV-1 infection and pathogenesis. IMPORTANCE How Vpr enhances HIV-1 replication in macrophages is still unclear. We report here that Vpr enhanced HIV-1 Env processing during the first round of HIV-1 replication, resulting in virions with higher Env incorporation and viral infectivity. These higher-quality viral particles contributed to elevated infection during the second round and spreading infection in macrophages and other HIV-1 target cells. We have recently discovered that TET2 is a novel host factor degraded by Vpr, which leads to sustained IL-6 expression in macrophages. Interestingly, Vpr-enhanced HIV-1 Env processing depended on both the IFITIM3 and TET2 genes. The constitutive expression of IFITIM3 expression in macrophages was maintained by TET2, which demethylated the IFITIM3 promoter. We conclude that the Vpr degrades TET2 to enhance HIV-1 replication in macrophages by reducing IFITIM3 expression to increase viral Env processing, virion incorporation, and infectivity and by sustaining IL-6 expression to increase HIV-1 gene expression. The Vpr-TET2 axis may serve as a novel target to develop anti-HIV drugs to inhibit HIV-1 infection and pathogenesis.

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“…Multiple studies have shown that DCAF1 fragments overlapping the WD40 motif can associate with DDB1 (Le Rouzic et al, 2008; McCall et al, 2008; Cassiday et al, 2015). However, a minimal fragment containing only the residues comprising the seven-bladed β-propeller motif of DCAF1 fails to bind DDB1, suggesting another interface helps stabilize the interaction with DDB1 (Cassiday et al, 2015). DDB1 itself is comprised of three WD40 β-propeller domains (designated BPA, BPB, and BPC) which adopt a planar, three-bladed conformation.…”

Section: Domain Organization Of Dcaf1 and Structural Characterizationmentioning

confidence: 99%

DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor

Schabla

Mondal

Swanson

2018

Journal of Molecular Cell Biology

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Cullin-RING ligases (CRLs) comprise a large group of modular eukaryotic E3 ubiquitin ligases. Within this family, the CRL4 ligase (consisting of the Cullin4 [CUL4] scaffold protein, the Rbx1 RING finger domain protein, the DNA damage-binding protein 1 [DDB1], and one of many DDB1-associated substrate receptor proteins) has been intensively studied in recent years due to its involvement in regulating various cellular processes, its role in cancer development and progression, and its subversion by viral accessory proteins. Initially discovered as a target for hijacking by the human immunodeficiency virus accessory protein r, the normal targets and function of the CRL4 substrate receptor protein DDB1–Cul4-associated factor 1 (DCAF1; also known as VprBP) had remained elusive, but newer studies have begun to shed light on these questions. Here, we review recent progress in understanding the diverse physiological roles of this DCAF1 in supporting various general and cell type-specific cellular processes in its context with the CRL4 E3 ligase, as well as another HECT-type E3 ligase with which DCAF1 also associates, called EDD/UBR5. We also discuss emerging questions and areas of future study to uncover the dynamic roles of DCAF1 in normal physiology.

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Understanding the molecular manipulation of DCAF1 by the lentiviral accessory proteins Vpr and Vpx

Cited by 9 publications

References 52 publications

CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation

CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation

Vpr Enhances HIV-1 Env Processing and Virion Infectivity in Macrophages by Modulating TET2-Dependent IFITM3 Expression

DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor

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