An unresolved question is how HIV‐1 achieves efficient replication in terminally differentiated macrophages despite the restriction factor SAMHD1. We reveal inducible changes in expression of cell cycle‐associated proteins including MCM2 and cyclins A, E, D1/D3 in macrophages, without evidence for DNA synthesis or mitosis. These changes are induced by activation of the Raf/MEK/ERK kinase cascade, culminating in upregulation of CDK1 with subsequent SAMHD1 T592 phosphorylation and deactivation of its antiviral activity. HIV infection is limited to these G1‐like phase macrophages at the single‐cell level. Depletion of SAMHD1 in macrophages decouples the association between infection and expression of cell cycle‐associated proteins, with terminally differentiated macrophages becoming highly susceptible to HIV‐1. We observe both embryo‐derived and monocyte‐derived tissue‐resident macrophages in a G1‐like phase at frequencies approaching 20%, suggesting how macrophages sustain HIV‐1 replication in vivo. Finally, we reveal a SAMHD1‐dependent antiretroviral activity of histone deacetylase inhibitors acting via p53 activation. These data provide a basis for host‐directed therapeutic approaches aimed at limiting HIV‐1 burden in macrophages that may contribute to curative interventions.

A subclass of zinc finger proteins containing a unique protein motif called the positive regulatory (PR) domain has been described. The members include the PRDI-BF1͞ Blimp-1 protein, the Caenorhabditis elegans egl-43 and EVI1 gene products, and the retinoblastoma interacting protein RIZ. Here we describe a member of this family, SC-1, that exhibits several distinctive features. First, SC-1 interacts with the p75 neurotrophin receptor and is redistributed from the cytoplasm to the nucleus after nerve growth factor (NGF) treatment of transfected COS cells. The translocation of SC-1 to the nucleus was specific for p75, as NGF binding to the TrkA receptor did not lead to nuclear localization of SC-1. Thus, SC-1 provides a downstream transducer for the effects of NGF through the p75 neurotrophin receptor. Under normal growth conditions, SC-1 was found predominantly in the cytoplasm. On serumstarvation, SC-1 also translocated into the nucleus. A direct correlation between nuclear expression of SC-1 with the loss of BrdUrd incorporation was observed. These results imply that SC-1 may be involved in events associated with growth arrest.Neurotrophins influence a wide number of functions in the nervous system, including neuronal cell survival, cell differentiation and apoptosis, synaptic plasticity, and control of axonal guidance and dendritic cell growth (1-3). These actions are mediated by neurotrophin binding to two separate receptor classes, the Trk family of tyrosine kinase receptors and the p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily. Nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin 4͞5 and neurotrophin 3 bind to TrkA, TrkB, and TrkC, respectively, whereas each neurotrophin is capable of binding to p75 with a similar affinity (4). In the presence of TrkA receptor, p75 can participate in the formation of high affinity binding sites and enhanced neurotrophin responsiveness leading to increased cell survival (5). In the absence of TrkA receptors, p75 can activate NF-B and JNK activities and can generate, in specific cell populations and conditions, a death signal (6-9). This dichotomy in responses has raised questions regarding the nature of the signaling mechanisms and how specificity for the two neurotrophin receptors is encoded.To elucidate the function of p75, an extensive two-hybrid screen was undertaken to identify proteins that interact with the cytoplasmic domain of p75. Such candidate molecules could reveal insight into the signal transduction mechanisms mediated by neurotrophins through the p75 receptor. One of the clones identified by this screen encoded a protein called SC-1 that contains six zinc finger domains and a unique domain, the positive regulatory (PR) or PRDI-BF1 and RIZ homology domain. The PR domain was previously identified as a common motif in several transcription factors, including RIZ and PRDI-BF1 (10, 18). Here, we describe the structural features of SC-1, its association with p75 neurotrophin receptor, and its...

Background: Neural stem cells generate all the cell types of the central nervous system.Results: Transcription factor, PRDM4, recruits protein arginine methyltransferase 5 (PRMT5) to control the timing of neurogenesis.Conclusion: PRDM4- and PRMT5-mediated histone arginine methylation controls neural stem cell proliferation and differentiation.Significance: Histone arginine methylation is a novel epigenetic mechanism that regulates neural stem cell reprogramming.

Schwann cell factor 1 (SC1), a p75 neurotrophin receptor–interacting protein, is a member of the positive regulatory/suppressor of variegation, enhancer of zeste, trithorax (PR/SET) domain-containing zinc finger protein family, and it has been shown to be regulated by serum and neurotrophins. SC1 shows a differential cytoplasmic and nuclear distribution, and its presence in the nucleus correlates strongly with the absence of bromodeoxyuridine (BrdU) in these nuclei. Here, we investigated potential transcriptional activities of SC1 and analyzed the function of its various domains. We show that SC1 acts as a transcriptional repressor when it is tethered to Gal4 DNA-binding domain. The repressive activity requires a trichostatin A–sensitive histone deacetylase (HDAC) activity, and SC1 is found in a complex with HDACs 1, 2, and 3. Transcriptional repression exerted by SC1 requires the presence of its zinc finger domains and the PR domain. Additionally, these two domains are involved in the efficient block of BrdU incorporation by SC1. The zinc finger domains are also necessary to direct SC1's nuclear localization. Lastly, SC1 represses the promoter of a promitotic gene, cyclin E, suggesting a mechanism for how growth arrest is regulated by SC1.

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