Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor

Genes Dev. 2012 Jul 15;26(14):1527-32. doi: 10.1101/gad.190157.112.

Abstract

Latent herpes simplex virus-1 (HSV1) genomes in peripheral nerve ganglia periodically reactivate, initiating a gene expression program required for productive replication. Whether molecular cues detected by axons can be relayed to cell bodies and harnessed to regulate latent genome expression in neuronal nuclei is unknown. Using a neuron culture model, we found that inhibiting mTOR, depleting its regulatory subunit raptor, or inducing hypoxia all trigger reactivation. While persistent mTORC1 activation suppressed reactivation, a mutant 4E-BP (eIF4E-binding protein) translational repressor unresponsive to mTORC1 stimulated reactivation. Finally, inhibiting mTOR in axons induced reactivation. Thus, local changes in axonal mTOR signaling that control translation regulate latent HSV1 genomes in a spatially segregated compartment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Axons / metabolism*
  • Axons / virology
  • Cells, Cultured
  • Genome, Viral / physiology
  • Herpes Simplex / genetics
  • Herpes Simplex / metabolism*
  • Herpesvirus 1, Human / physiology*
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes
  • Proteins / genetics
  • Proteins / metabolism
  • Rats
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Virus Latency / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Multiprotein Complexes
  • Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Mechanistic Target of Rapamycin Complex 1