SAMHD1 restricts human immunodeficiency virus-1 (HIV-1) infection of dendritic and other myeloid cells at an early stage in the replication cycle. SIVsm/HIV-2 lineage viruses counteract SAMHD1-mediated restriction by encoding Vpx, a virion-packaged accessory protein that targets SAMHD1 for degradation. We show that SAMHD1 restricts HIV-1 infection of monocyte-derived macrophages (MDM) by hydrolyzing the cellular deoxynucleotide triphosphates (dNTP), reducing their level to below that required for the synthesis of the viral genomic DNA. Vpx prevented the SAMHD1-mediated decrease in dNTP. The restriction was partially alleviated in MDM by the addition of exogenous deoxynucleosides. HIV-1 with a V148I mutation in reverse transcriptase that lowers its affinity for dNTP was particularly sensitive to SAMHD1-mediated restriction. Nucleotide starvation could serve as a mechanism to protect cells from infection by a wide variety of infectious agents that replicate through a DNA intermediate.
The epithelial to mesenchymal transition (EMT) is an essential process during development and during tumor progression. Here, we observed the accumulation of the selective autophagy receptor and signaling adaptor sequestosome-1 (SQSTM1/p62) during growth factor-induced EMT in immortalized and tumor-derived epithelial cell lines. Modulation of the p62 level regulated the expression of junctional proteins. This effect was dependent on the ubiquitin-associated domain of p62, which stabilized the TGFβ/Smad signaling co-activator Smad4 and the EMT transcription factor Twist. This study highlights a novel function of p62 in a major epithelial phenotypic alteration.
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