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Human cytomegalovirus overcomes SAMHD1 restriction in macrophages via pUL97

Abstract

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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Fig. 1: SAMHD1 restricts HCMV replication in MDMs.
Fig. 2: SAMHD1 steady-state expression is reduced in HCMV-infected MDMs.
Fig. 3: HCMV interferes with SAMHD1 in an IFN-independent manner.
Fig. 4: HCMV-infected MDMs show elevated p-SAMHD1 T592.
Fig. 5: SAMHD1 T592 phosphorylation is induced by HCMV and mediated by CDKs.
Fig. 6: The HCMV-encoded kinase pUL97 phosphorylates SAMHD1.

Data availability

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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Acknowledgements

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.

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R.B., J.D., I.G., L.W., T.G. and M.S. designed experiments. R.B. peformed the infection and the IFN-α experiments, FACS measurements and RT–qPCR. Transfection experiments and in vitro kinase assays were done by J.D., I.G. and L.W. R.B., J.D., I.G., L.W., T.G. and M.S. analysed the data. J.M., L.W., T.G. and M.S. contributed reagents and analysis tools. R.B. and M.S. wrote the manuscript. M.S. conceived the overall study and developed the manuscript to its final form. All authors contributed to manuscript editing, read and approved the final manuscript draft.

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Correspondence to Michael Schindler.

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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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