Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor.
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.
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Mariko
M
Kobayashi
Angus C
AC
Wilson
Moses V
MV
Chao
Ian
I
Mohr
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D016679:Genome, Viral / Q000502:physiology; D006561:Herpes Simplex / Q000235:genetics / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D011506:Proteins; C546845:mTOR protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases