Cytomegalovirus disrupts Lamin A/C to control microtubule-mediated nuclear movement and cell migration

Jamil Mahmud1, Ipsita Nandi1, Dean J Procter1

  • 1Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.

Insights

Human cytomegalovirus (HCMV) manipulates Lamin A/C and SUN2 to control nuclear movement and cell migration. HCMV selectively downregulates these proteins to enable acetylated microtubules, crucial for cell migration during infection.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Human cytomegalovirus (HCMV) infection alters nuclear architecture.
  • Lamin A/C and SUN2 are key components of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex.
  • LINC complexes connect the nuclear envelope to the cytoskeleton, influencing nuclear positioning and cell migration.

Purpose of the Study:

  • To investigate the role of Lamin A/C and SUN2 in HCMV-induced nuclear movement and cell migration.
  • To elucidate the mechanisms by which HCMV manipulates Lamin A/C and SUN2 during infection.
  • To understand how HCMV controls cytoskeletal interactions with the nucleus.

Main Methods:

  • Studied HCMV-infected cells.
  • Investigated the expression levels of Lamin A/C and SUN2.
  • Assessed the impact of viral kinase pUL97 inhibition and Lamin A/C mutants on protein expression and cytoskeletal organization.
  • Examined the effects of SUN2 or Lamin A/C re-expression.
  • Analyzed the role of acetylated microtubules in nuclear movement and cell migration.
  • Depleted the tubulin acetyl transferase ATAT1.

Main Results:

  • HCMV downregulates Lamin A/C and SUN2 to facilitate virion egress and later-stage nuclear-cytoskeletal rewiring.
  • Inhibition of viral kinase pUL97 or expression of nonphosphorylatable Lamin A/C mutants did not restore SUN2 expression or actin assembly.
  • Exogenous re-expression of SUN2 or Lamin A/C impaired acetylated microtubule formation.
  • Inhibition of pUL97, Lamin A/C mutants, or ATAT1 depletion impaired HCMV-induced nuclear movement and cell migration.

Conclusions:

  • HCMV employs multiple strategies to downregulate Lamin A/C and SUN2.
  • These downregulations prevent interference with acetylated microtubule formation, which is essential for nuclear movement and cell migration.
  • Reveals novel roles for Lamin A/C remodeling in HCMV infection and provides insights into nuclear-cytoskeletal control.

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