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Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication

R van Domselaar1, S A H de Poot, E B M Remmerswaal

  • 1Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Cell Death and Differentiation
|October 27, 2012
PubMed

Insights

Cytotoxic lymphocytes use granzyme M (GrM) to control human cytomegalovirus (HCMV) by targeting the host protein hnRNP K. This mechanism reduces viral replication by lowering essential IE2 protein levels.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Human cytomegalovirus (HCMV) is a significant cause of congenital defects and severe disease in immunocompromised individuals.
  • Cytotoxic lymphocytes, particularly CD8(+) T cells, are crucial for controlling HCMV infection through granzyme-mediated killing.
  • The specific mechanisms by which granzymes, like granzyme M (GrM), control HCMV remain incompletely understood.

Purpose of the Study:

  • To investigate the role of human GrM in controlling HCMV infection.
  • To identify physiological substrates of GrM during HCMV infection.
  • To elucidate the mechanism by which GrM-mediated targeting of host factors inhibits viral replication.

Main Methods:

  • Detection of GrM expression in HCMV-specific CD8(+) T cells from infected individuals.
  • Identification and characterization of GrM substrates using biochemical assays.
  • Analysis of the role of identified substrates in HCMV replication and viral protein regulation.
  • Assessment of GrM's effect on viral gene expression in infected cells.

Main Results:

  • Human GrM was expressed by HCMV-specific CD8(+) T cells in latently infected individuals and during primary infection in transplant patients.
  • Heterogeneous nuclear ribonucleoprotein K (hnRNP K) was identified as a physiological substrate of GrM.
  • GrM cleaved hnRNP K, likely impairing its function, and hnRNP K was essential for HCMV replication by supporting cell viability and regulating viral immediate-early 2 (IE2) protein levels.
  • hnRNP K interacted with IE2 mRNA, and GrM reduced IE2 protein expression in HCMV-infected cells.

Conclusions:

  • GrM targets the host protein hnRNP K to inhibit HCMV replication.
  • This targeting mechanism contributes to cytotoxic lymphocyte-mediated control of HCMV.
  • This study provides the first evidence of cytotoxic lymphocytes targeting host cell proteins to control HCMV infections.

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