The host restriction factor sterile alpha motif and histidine–aspartate domain-containing protein 1 (SAMHD1) is an important component of the innate immune system. By regulating the intracellular nucleotide pool, SAMHD1 influences cell division and restricts the replication of viruses that depend on high nucleotide concentrations. Human cytomegalovirus (HCMV) is a pathogenic virus with a tropism for non-dividing myeloid cells, in which SAMHD1 is catalytically active. Here we investigate how HCMV achieves efficient propagation in these cells despite the SAMHD1-mediated dNTP depletion. Our analysis reveals that SAMHD1 has the capability to suppress HCMV replication. However, HCMV has evolved potent countermeasures to circumvent this block. HCMV interferes with SAMHD1 steady-state expression and actively induces SAMHD1 phosphorylation using the viral kinase pUL97 and by hijacking cellular kinases. These actions convert SAMHD1 to its inactive phosphorylated form. This mechanism of SAMHD1 inactivation by phosphorylation might also be used by other viruses to overcome intrinsic immunity.
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All data generated and analysed during this study are included in this published manuscript. Further datasets supporting this study are available from the corresponding author upon request.
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The authors thank K. Hamprecht for help, critical reading of the manuscript and fruitful discussions, as well as support in measuring and quantifying HCMV genomes; K. Kollender, I. Krotova and S. Wagner for technical assistance; T. Iftner for support and encouragement; the ImageStream and FACS Core Facility of the UKT for help with imaging flow cytometry and cell sorting; the team of the Transfusion Medicine Tübingen (ZKT, T. Bakchoul) for providing Buffy Coat and C. Sinzger, M. Marschall, B. Vetter, M. Winkler and R. Kalejta for providing HCMV constructs and protein kinase inhibitors as well as helpful comments and suggestions. This work was funded in part by basic research support given from the University Hospital Tübingen, Medical Faculty and a DFG (SCHI1073/7-1) grant within the SPP1923 ‘Innate Sensing and Restriction of Retroviruses’ to M.S. T.G. (GR3355/3-1) and J.M. (MI2143/2-1) are also supported by research grants from the DFG. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
The authors declare no competing interests.
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Businger, R., Deutschmann, J., Gruska, I. et al. Human cytomegalovirus overcomes SAMHD1 restriction in macrophages via pUL97. Nat Microbiol 4, 2260–2272 (2019). https://doi.org/10.1038/s41564-019-0557-8
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