Human cytomegalovirus overcomes SAMHD1 restriction in macrophages via pUL97

Businger, Ramona; Deutschmann, Janina; Gruska, Iris; Milbradt, Jens; Wiebusch, Lüder; Gramberg, Thomas; Schindler, Michael

doi:10.1038/s41564-019-0557-8

Cited by 39 publications

(73 citation statements)

References 77 publications

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“…Notably, pUL97 phosphorylates several viral and cellular proteins (see horizontal bars in Figure 1 for those binding regions within pUL97 that have been mapped thus far), including the viral DNA polymerase cofactor pUL44 [122], viral RNA transport factor pUL69 [79], major tegument protein pp65 [95], nuclear egress core proteins pUL50-pUL53 [99,127], cellular multiligand binding protein p32/gC1qR [98,122], tumor suppressor protein Rb [75], nuclear lamins A/C [57,84,94,98,129], RNAP II [100], translation factor EF-1δ [63,101,130], interferon-inducible, intrinsic immune restriction factors IFI16 [96] and SAMHD1 [105] (Figure 2; Table 3; compare with Tables S1, S2 and S3). It should be emphasized that the pUL97 substrate proteins belong to several functionally different groups (Table 3), thus underlining the multifunctional nature of this singly expressed viral protein kinase.…”

Section: Phosphorylation Of a Panel Of Regulatory Viral Proteins And mentioning

confidence: 99%

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

Steingruber

Marschall

2020

Microorganisms

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Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of viral and cellular substrates. A hierarchy of functional importance of individual pUL97-mediated phosphorylation events has been discussed; however, the most pronounced pUL97-dependent phenotype could be assigned to viral nuclear egress, as illustrated by deletion of the UL97 gene or pharmacological pUL97 inhibition. Despite earlier data pointing to a cyclin-independent functionality, experimental evidence increasingly emphasized the role of pUL97-cyclin complexes. Consequently, the knowledge about pUL97 involvement in host interaction, viral nuclear egress and additional replicative steps led to the postulation of pUL97 as an antiviral target. Indeed, validation experiments in vitro and in vivo confirmed the sustainability of this approach. Consequently, current investigations of pUL97 in antiviral treatment go beyond the known pUL97-mediated ganciclovir prodrug activation and henceforward include pUL97-specific kinase inhibitors. Among a number of interesting small molecules analyzed in experimental and preclinical stages, maribavir is presently investigated in clinical studies and, in the near future, might represent a first kinase inhibitor applied in the field of antiviral therapy.

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Section: Phosphorylation Of a Panel Of Regulatory Viral Proteins And mentioning

confidence: 99%

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

Steingruber

Marschall

2020

Microorganisms

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“…In another virus, human CMV, NF-κB activation is blocked during the early steps of infection, thereby, leading to limited SAMHD1 inhibition [16]. Also, in human CMV and herpesvirus, the viral kinases pUL97 and BGLF4 phosphorylate SAMHD1 and inactivate the restriction, respectively [17,18].…”

Section: Introductionmentioning

confidence: 99%

Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1

et al. 2020

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SAMHD1 is an enzyme with phosphohydrolase activity. Mutations in SAMHD1 have been linked to the development of Aicardi‐Goutières syndrome in humans. This enzyme also has the capacity to restrict HIV virus replication in macrophages. Here, we report that Samhd1 is highly expressed in murine macrophages and is regulated by proinflammatory (IFN‐γ and LPS) but not by anti‐inflammatory (IL‐4 or IL‐10) activators. The induction of Samhd1 follows the pattern of an intermediate gene that requires protein synthesis. In transient transfection experiments using the Samhd1 promoter, we found that a fragment of 27 bps of this gene, falling between −937 and −910 bps relative to the transcription start site, is required for IFN‐γ‐dependent activation. Using EMSAs, we determined that IFN‐γ treatment led to the elimination of a protein complex. Chromatin immunoprecipitation assays and siRNA experiments revealed that IRF1 is required for IFN‐γ‐ or LPS‐induced Samhd1 expression. Therefore, our results indicate that Samhd1 is stimulated by proinflammatory agents IFN‐γ and LPS. Moreover, they reveal that these two agents, via IRF1, eliminate a protein complex that may be related to a repressor, thereby, triggering Samhd1 expression.

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“…For generating HCMV stocks HFF cells were infected with TB40-ΔUL16-eGFP essentially as described before (35). Infectious supernatant was harvested 5 to 7 dpi and subsequently cleared from cells and cellular debris by centrifuging 10 min at 3200 x g.…”

Section: Methodsmentioning

confidence: 99%

The human α-defensin-derived peptide HD5(1-9) inhibits cellular attachment and entry of human cytomegalovirus

Böffert

Businger

Preiß

et al. 2019

Preprint

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AUTHOR SUMMARY 49Defensins are peptides produced by various human organs which take part in the 50 natural defense against pathogens. Recently, it has been shown that defensins are 51 further cleaved to smaller peptides that have high intrinsic anti-microbial activity. We 52 here challenged the hypothesis that these peptides might have antiviral activity, and due 53 to their presumably natural occurrence, low toxicity. Indeed, we found one peptide 54 fragment that turned out to block the attachment of the human cytomegalovirus (HCMV) 55 to cells. Furthermore, this peptide did not show toxicity in various cellular assays or 56 impede the embryonic development of zebrafish at the concentrations used to block 57 HCMV. This is important, since HCMV is one of the most important viral congenital 58 infections. Altogether, our results hold promise for the development of a new class of 59 antivirals against HCMV.

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Human cytomegalovirus overcomes SAMHD1 restriction in macrophages via pUL97

Cited by 39 publications

References 77 publications

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1

The human α-defensin-derived peptide HD5(1-9) inhibits cellular attachment and entry of human cytomegalovirus

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