Lens Epithelium-derived Growth Factor/p75 Prevents Proteasomal Degradation of HIV-1 Integrase

Abstract

The transcriptional coactivator lens epithelium-derived growth factor (LEDGF)/p75 acts as a chromatin tethering factor for human immunodeficiency virus type 1 (HIV-1) integrase protein, determining its nuclear localization and its tight association with nuclear DNA. Here we identify a second function for the LEDGF/p75-integrase interaction. We observed that stable introduction of HIV-1 integrase (

Integrase, LEDGF/p75 and HIV replication

“…In contrast, in p75-deficient cell lines IN was barely detectable despite IN mRNA levels equivalent to non-deficient cells [78]. p75 re-expression rescued IN expression while neither p52 nor IBD-deleted p75 were effective [78]. Moreover, it is clear that the location of the IN-p75 complex in the cell is irrelevant, since a nuclear localization signal-mutant version p75, which complexed with IN in the cytoplasm, still provides robust protection from degradation [78,80].…”

“…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.…”

“…In addition to chromatin tethering, and mechanistically separable from it, there is a second outcome of the p75-IN interaction: a striking increase in IN stability [78]. HIV IN is ubiquitylated and is subject to degradation in the proteasome [78,123,145].…”

“…HIV IN is ubiquitylated and is subject to degradation in the proteasome [78,123,145]. Nevertheless it is readily expressed from the IN cDNA at substantial levels provided Rev-dependence is taken into account [75].…”

“…Nevertheless it is readily expressed from the IN cDNA at substantial levels provided Rev-dependence is taken into account [75]. In contrast, in p75-deficient cell lines IN was barely detectable despite IN mRNA levels equivalent to non-deficient cells [78]. p75 re-expression rescued IN expression while neither p52 nor IBD-deleted p75 were effective [78].…”