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<p>Varicella-zoster virus (VZV) infects most humans and causes chickenpox, shingles and central nervous system pathologies. The molecular basis for these phenotypes remains elusive. Here we conducted a multi-proteomic survey on 64 individual VZV proteins and infection-induced perturbations in a neuronal cell line, identifying 900 interactors and 3,618 regulated host proteins. Data integration suggested molecular functions of viral proteins, such as a mechanism for the ORF61-mediated IFI16 degradation via the recruitment of E3 ligase co-factors. Moreover, we identified proviral host factors (MPP8 and ZNF280D) as potential targets to limit infection. Integration of exome sequencing analysis from patients with VZV-associated central nervous system pathologies identified nephrocystin 4 as a viral restriction factor, and its S862N variant, which showed reduced activity and decreased binding to the regulatory proteins 14-3-3. Collectively, our study provides a comprehensive herpesvirus–host interface resource, which aids our understanding of disease-associated molecular perturbations and data-driven identification of antiviral treatment options.</p>

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Multi-proteomic profiling of the varicella-zoster virus–host interface reveals host susceptibilities to severe infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月30日

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  • Virginie Girault,
  • Alexey Stukalov,
  • Madalina Elena Carter-Timofte,
  • Jonny Hertzog,
  • Melissa Verin,
  • Katharina Austen,
  • Darya A. Haas,
  • Lila Oubraham,
  • Antonio Piras,
  • Susanne Maidl,
  • Rupert Öllinger,
  • Roland Rad,
  • Ulrike Protzer,
  • Benedikt B. Kaufer,
  • Robert J. Lebbink,
  • Jan Rehwinkel,
  • Trine H. Mogensen,
  • Andreas Pichlmair

摘要

Varicella-zoster virus (VZV) infects most humans and causes chickenpox, shingles and central nervous system pathologies. The molecular basis for these phenotypes remains elusive. Here we conducted a multi-proteomic survey on 64 individual VZV proteins and infection-induced perturbations in a neuronal cell line, identifying 900 interactors and 3,618 regulated host proteins. Data integration suggested molecular functions of viral proteins, such as a mechanism for the ORF61-mediated IFI16 degradation via the recruitment of E3 ligase co-factors. Moreover, we identified proviral host factors (MPP8 and ZNF280D) as potential targets to limit infection. Integration of exome sequencing analysis from patients with VZV-associated central nervous system pathologies identified nephrocystin 4 as a viral restriction factor, and its S862N variant, which showed reduced activity and decreased binding to the regulatory proteins 14-3-3. Collectively, our study provides a comprehensive herpesvirus–host interface resource, which aids our understanding of disease-associated molecular perturbations and data-driven identification of antiviral treatment options.