LEDGF/p75 Is Essential for Nuclear and Chromosomal Targeting of HIV-1 Integrase in Human Cells

Maertens, Goedele N.; Cherepanov, Peter; Pluymers, W; Busschots, Katrien; Clercq, Erik De; Debyser, Zeger; Engelborghs, Yves

doi:10.1074/jbc.m303594200

Cited by 445 publications

(566 citation statements)

References 66 publications

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“…5a) did alter the cellular distribution of Flag-IWS1. This is in contrast to earlier reports on the LEDGF/p75 interactors JPO2 and HIV IN 30,33,45 .…”

Section: Jpo2 Interacts With the Ibd Through A Disordered Regioncontrasting

confidence: 99%

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

et al. 2015

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Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors.

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“…5a) did alter the cellular distribution of Flag-IWS1. This is in contrast to earlier reports on the LEDGF/p75 interactors JPO2 and HIV IN 30,33,45 .…”

Section: Jpo2 Interacts With the Ibd Through A Disordered Regioncontrasting

confidence: 99%

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

et al. 2015

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“…Second, when p75 was depleted by RNAi, integrase shifted completely to the cytoplasm (Fig. 4b) [74,75]). Third, IN mutants that are unable to interact with p75 lose chromatin association [86].…”

Section: Interaction With Lentiviral Integrase Proteins and The Traffmentioning

confidence: 98%

“…The interaction between p75 and IN is direct [73] and it is confined to only one of the seven retroviral genera, lentivirinae [75,87,100]. A number of laboratories established the role of p75 in chromatin tethering, mapped relevant functional domains, and worked to answer the question of virological relevance [74][75][76][77][78][79][80][81][82][85][86][87][88][89][90][91]93,[95][96][97][100][101][102][103][104][105][108][109][110]. The first indication of the protein's significance was the clarification it provided about the vexing issue of the intracellular trafficking of retroviral integrase proteins.…”

Section: Interaction With Lentiviral Integrase Proteins and The Traffmentioning

confidence: 99%

“…The first indication of the protein's significance was the clarification it provided about the vexing issue of the intracellular trafficking of retroviral integrase proteins. When HIV IN is expressed outside the viral context it is karyophilic [118][119][120][121] and chromatin-associated [73][74][75]86,122,123]. This property is characteristic of the entire lentivirus genus since IN proteins from the two nonprimate (feline and ungulate) subgenera behave identically [75,87,100].…”

Section: Interaction With Lentiviral Integrase Proteins and The Traffmentioning

confidence: 99%

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Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

115

104

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HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene therapy.

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“…In the presence of LEDGF/p75, HIV-1 IN and viral DNA form tetramer and then transport to nucleus and initiate strand transfer reaction (McKee et al 2008). LEDGF/p75 protects the viral protein from degrading by proteosomal enzymes in human cell (Maertens et al 2003;Emiliani et al 2005). However the exact role of LEDGF/ p75 in the HIV-1 infection is still ambiguous.…”

Section: Introductionmentioning

confidence: 99%

Biochemical functions of integrase-binding domain of lens epithelium-derived growth factor

Kim

Hamid

Shin

2015

Animal Cells and Systems

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Integrase-binding domain (IBD) is a critical region on the lens epithelium-derived growth factor (LEDGF/p75) protein that specifically interacts with human immunodeficiency virus type 1 integrase (HIV-1 IN). In this study, we expressed and purified the IBD, and utilized in endonucleolytic assay and strand transfer assay to investigate whether IBD improve enzymatic activities of HIV-1 IN. Our results showed that IBD along with HIV-1 IN increased the strand transfer activity but not the endonucleolytic activity. Furthermore, our results showed that IBD induced efficient integration of the donor DNA into the target DNA to create half-site integration and full-site integration using plasmid as target DNA. Therefore, it is suggested that LEDGF-IBD itself might be able to increase viral infectivity by enhancing the strand transfer activities of HIV-1 IN and accelerating integration of viral cDNA into cellular chromosomal DNA.

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LEDGF/p75 Is Essential for Nuclear and Chromosomal Targeting of HIV-1 Integrase in Human Cells

Abstract: We have reported that human immunodeficiency virus type 1 (HIV-1) integrase (IN) forms a specific nuclear complex with human lens epithelium-derived growth factor/transcription co-activator p75 (LEDGF/p75) protein. We now studied

Cited by 445 publications

References 66 publications

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

Integrase, LEDGF/p75 and HIV replication

Biochemical functions of integrase-binding domain of lens epithelium-derived growth factor

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