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Human cytomegalovirus protein UL13 targets to mitochondria to induce cuproptosis

Xin-Mei Yang1, Ya-Li Lei1, Yu Zhang1

  • 1Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Hubei Provincial Research Center for Basic Biological Sciences, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.

Biochemical and Biophysical Research Communications
|July 13, 2025
PubMed

Insights

Human cytomegalovirus (HCMV) protein UL13 triggers a copper-dependent cell death pathway called cuproptosis. This virus hijacks mitochondrial copper transport, impacting viral pathogenesis.

Area of Science:

  • Virology
  • Cell Biology
  • Biochemistry

Background:

  • Human cytomegalovirus (HCMV) is a significant pathogen, particularly in immunocompromised individuals.
  • HCMV employs sophisticated mechanisms to manipulate host cell functions for replication and immune evasion.

Purpose of the Study:

  • To investigate the role of HCMV protein UL13 in host cell death pathways.
  • To elucidate the molecular mechanisms by which HCMV interacts with host cell processes.

Main Methods:

  • Overexpression and knockdown of HCMV UL13.
  • Analysis of cuproptosis hallmarks: DLAT oligomerization, Fe-S cluster protein levels, and mitochondrial copper.
  • Mitochondrial localization studies of UL13.
  • Investigation of UL13 interaction with SLC25A3.
  • SLC25A3 knockout experiments.

Main Results:

  • HCMV UL13 induces cuproptosis, characterized by DLAT oligomerization, Fe-S cluster depletion, and mitochondrial copper accumulation.
  • UL13 localizes to mitochondria and interacts with the copper transporter SLC25A3.
  • UL13-induced mitochondrial copper overload is essential for DLAT oligomerization and cell death.
  • UL13 knockdown inhibits HCMV-induced cuproptosis.

Conclusions:

  • HCMV protein UL13 is a potent inducer of cuproptosis.
  • HCMV exploits host copper homeostasis via UL13 and SLC25A3 to induce cell death.
  • This study reveals a novel mechanism of viral pathogenesis linked to copper metabolism.
Keywords:
CuproptosisHuman cytomegalovirusSLC25A3UL13

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