Highlights d The NIPBL-MAU2 interaction is required for the stability of both proteins d A pathogenic MAU2 deletion impairs dimerization and causes NIPBL haploinsufficiency d Early frameshift mutations in NIPBL induce alternative translation initiation d Translation re-initiation rescues NIPBL expression and renders MAU2 dispensable
A major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular determinants of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has been challenging. Here we use a dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to probe the differential protein composition of the latent and activated HIV-1 5′LTR. Catchet-MS identified known and novel latent 5′LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the clinically advanced thalidomide analogue iberdomide, and the FDA approved analogues lenalidomide and pomalidomide, to be novel LRAs. We demonstrate that, by targeting IKZF1 for degradation, these compounds reverse HIV-1 latency in CD4+ T-cells isolated from virally suppressed people living with HIV-1 and that they are able to synergize with other known LRAs.
A major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular correlates of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has not been possible. Here we use dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to isolate the latent and activated HIV-1 5′LTR, followed by MS identification of the differentially locus-bound proteins. Catchet-MS identified known and novel latent 5′LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the drug iberdomide, which targets IKZF1 for degradation, to be a clinically advanced novel LRA that reverses HIV-1 latency in CD4+T-cells isolated from virally suppressed HIV-1 infected participants.
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