During viral infection, the host subjects the virus to an array of protective mechanisms. Viruses have evolved evasion strategies to thwart these defenses, and must simultaneously regulate multiple cellular pathways and resources to achieve successful replication. To orchestrate such complex regulation, viruses, including herpes simplex virus 1 (HSV-1), rely on multifunctional proteins such as the E3 ubiquitin ligase ICP0. This protein counteracts various host defenses by targeting cellular factors for degradation. We undertook a proteomic screen to identify binding partners of ICP0, and identified the Tripartite Motif 27 (TRIM27) protein, a cellular transcriptional repressor, as a novel interacting protein of ICP0. This interaction resulted in rapid loss of TRIM27 during HSV-1 infection. However, replication of an ICP0-null mutant virus required TRIM27, suggesting a complex interaction between TRIM27 and viral infection.
To further characterize regulation of TRIM27 by HSV-1, we evaluated whether infection affected TRIM27 levels independently of ICP0. Infection with an ICP0-null virus resulted in TRIM27 protein loss, but at a greatly reduced rate. TRIM27 protein exhibited a short half-life in uninfected cells, indicating that viral regulation of transcript levels could affect protein levels during infection. HSV-1 reduced TRIM27 transcripts through the virion host shutoff (VHS) function and a global inhibition of host transcription. The compound regulation of TRIM27 levels during infection demonstrated the redundant mechanisms by which HSV-1 regulates the cellular proteome.
Because degradation targets of ICP0 often function to restrict viral infection, we hypothesized that TRIM27 could contribute to an antiviral pathway. Based on the involvement of TRIM27 in programmed cell death resulting from Tumor Necrosis Factor (TNF) signaling, we evaluated the role of TRIM27 in cells treated with TNF. TRIM27 was required for TNF-dependent programmed necrosis, or necroptosis, in mouse cells. HSV-1 infection of these cells induced TNF-dependent necroptosis, reducing viral yield. This pathway required mouse TRIM27, and cells expressing human TRIM27 in place of mouse TRIM27 did not exhibit necroptosis. The differing capacities of mouse and human TRIM27 to support necroptosis during HSV-1 infection suggested that TRIM27 contributes to species-specific restriction of HSV-1 and to the selective pressure driving viral evasion of this protective host response. / Medical Sciences
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/17463971 |
| Date | 01 May 2017 |
| Creators | Conwell, Sara |
| Contributors | Wang, Fred, Rabkin, Samuel, Chan, Francis, Knipe, David |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation, text |
| Format | application/pdf |
| Rights | open |
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