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Updated: Jan 29, 2026

Plaquing of Herpes Simplex Viruses
Published on: November 5, 2021
The Tumor Cell Proliferation Inhibitory Activity of the Human Herpes Virus Type 6 U94 Protein Relies on a Stable
Anna Bertelli1, Matteo Uggeri2, Federica Filippini1
1Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Abstract:
The U94 protein of Human Herpesvirus 6 exerts antiproliferative effects through downregulation of the Src proto-oncogene. We aimed to define the shortest U94 fragment that preserves antiproliferative activity and to explore its structural properties. U94 was truncated into shorter fragments, which were subjected to computational analyses and proliferation assays on MDA-MB-468, BT-549 breast cancer cells. Src phosphorylation levels were scrutinized by Western blot analysis. Data obtained demonstrated that the U94 antiproliferative activity resides in its N-terminal region. Specifically, MT153 (aa 1-153) and MT117 (aa 1-117) fragments exhibited antiproliferative activity, whereas MV85 (aa 1-85) fragment did not. Computational analyses identified MG112 (aa 1-112) and MI108 (aa 1-108) as biologically active and suggested that the β-sheet of the structure is critical. The shortest KI95 fragment (aa 14-108), maintaining a stable β-sheet, demonstrated antiproliferative effects and Src downregulation. The antiproliferative activity of U94 and its active fragments relies on stable tridimensional conformation rather than on linear peptide sequence. KI95 represents the shortest active U94 fragment that preserves biological function, with critical residues likely located within the β-sheet region. These findings highlight the importance of structural integrity in U94 functionality and suggest KI95 as a potential therapeutic agent for cancer treatment.
Insights
The U94 protein from Human Herpesvirus 6 has anticancer properties. The shortest active fragment, KI95, maintains its antiproliferative effect by downregulating Src, highlighting the importance of structural conformation for therapeutic potential.
Area of Science:
- Molecular Biology
- Virology
- Oncology
Background:
- The U94 protein of Human Herpesvirus 6 (HHV-6) is known to inhibit cell proliferation by downregulating the Src proto-oncogene.
- Understanding the minimal functional domain of U94 is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To identify the shortest U94 protein fragment retaining antiproliferative activity.
- To investigate the structural characteristics essential for U94's biological function.
- To explore the potential of U94 fragments as therapeutic agents for cancer treatment.
Main Methods:
- Truncation of the U94 protein into various fragments.
- In vitro proliferation assays using breast cancer cell lines (MDA-MB-468, BT-549).
- Computational analyses to predict structural properties.
- Western blot analysis to assess Src phosphorylation levels.
Main Results:
- Antiproliferative activity was localized to the N-terminal region of U94.
- Fragments MT153 and MT117 showed activity, while MV85 did not.
- The shortest active fragment identified was KI95 (aa 14-108), which maintained antiproliferative effects and Src downregulation.
- Structural analysis indicated that a stable β-sheet conformation is critical for activity, rather than a specific linear sequence.
Conclusions:
- The antiproliferative function of U94 and its active fragments depends on their three-dimensional structure.
- KI95 is the shortest U94 fragment that retains biological activity, with key residues likely within its β-sheet region.
- These findings support the potential of KI95 as a novel therapeutic agent for cancers driven by Src activity.
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