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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
PML mediates the interferon-induced antiviral state against a complex retrovirus via its association with the viral
T Regad1, A Saib, V Lallemand-Breitenbach
1CNRS UPR 9051, Hôpital St Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
Abstract:
The promyelocytic leukaemia (PML) protein localizes in the nucleus both in the nucleoplasm and in matrix-associated multiprotein complexes known as nuclear bodies (NBs). The number and the intensity of PML NBs increase in response to interferon (IFN). Overexpression of PML affects the replication of vesicular stomatitis virus and influenza virus. However, PML has a less powerful antiviral activity against these viruses than the IFN mediator MxA. Here, we show that overexpression of PML, but not that of Mx1 or MxA, leads to a drastic decrease of a complex retrovirus, the human foamy virus (HFV), gene expression. PML represses HFV transcription by complexing the HFV transactivator, Tas, preventing its direct binding to viral DNA. This physical interaction requires the N-terminal region of Tas and the RING finger of PML, but does not necessitate PML localization in NBs. Finally, we show that IFN treatment inhibits HFV replication in wild-type but not in PML-/- cells. These findings point to a role for PML in transcriptional repression and suggest that PML could play a key role in mediating an IFN-induced antiviral state against a complex retrovirus.
Insights
Promyelocytic leukaemia (PML) protein represses human foamy virus (HFV) gene expression by inhibiting viral transcription. Interferon (IFN) treatment inhibits HFV replication in PML-expressing cells, highlighting PML's antiviral role.
Area of Science:
- Molecular Biology
- Virology
- Cell Biology
Background:
- The promyelocytic leukaemia (PML) protein localizes in the nucleus and forms nuclear bodies (NBs).
- PML NB formation and intensity increase upon interferon (IFN) stimulation.
- PML exhibits antiviral activity, though less potent than MxA against certain viruses.
Purpose of the Study:
- To investigate the role of PML in the gene expression and replication of complex retroviruses, specifically human foamy virus (HFV).
- To elucidate the mechanism by which PML affects HFV transcription.
- To determine if PML mediates the antiviral state induced by IFN against HFV.
Main Methods:
- Overexpression of PML, Mx1, and MxA in cells.
- Analysis of human foamy virus (HFV) gene expression.
- Assessment of viral DNA binding by the HFV transactivator, Tas.
- Experimental use of wild-type and PML-/- cells.
- Interferon (IFN) treatment of cells.
Main Results:
- Overexpression of PML, but not Mx1 or MxA, significantly decreased HFV gene expression.
- PML represses HFV transcription by binding to the HFV transactivator, Tas, preventing its DNA binding.
- This interaction requires the N-terminal region of Tas and the PML RING finger, independent of PML NB localization.
- IFN treatment inhibited HFV replication in wild-type cells but not in PML-/- cells.
Conclusions:
- PML plays a significant role in the transcriptional repression of complex retroviruses like HFV.
- PML directly interacts with the HFV transactivator, Tas, to inhibit viral transcription.
- PML is crucial for mediating an IFN-induced antiviral state against HFV, underscoring its importance in innate antiviral immunity.
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