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.

Microorganisms
|January 28, 2026
PubMed

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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