Dynamic ubiquitination drives herpesvirus neuroinvasion

Nicholas J. Huffmaster, Patricia J. Sollars, Alexsia L. Richards, Gary E. Pickard, Gregory A. Smith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Neuroinvasive herpesviruses display a remarkable propensity to enter the nervous system of healthy individuals in the absence of obvious trauma at the site of inoculation. We document a repurposing of cellular ubiquitin during infection to switch the virus between two invasive states. The states act sequentially to defeat consecutive host barriers of the peripheral nervous system and together promote the potent neuroinvasive phenotype. The first state directs virus access to nerve endings in peripheral tissue, whereas the second delivers virus particles within nerve fibers to the neural ganglia. Mutant viruses locked in either state remain competent to overcome the corresponding barrier but fail to invade the nervous system. The herpesvirus "ubiquitin switch" may explain the unusual ability of these viruses to routinely enter the nervous system and, as a consequence, their prevalence in human and veterinary hosts.

Original languageEnglish (US)
Pages (from-to)12818-12823
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
StatePublished - Oct 13 2015


  • HSV-1
  • Herpesvirus
  • Neuroinvasion
  • PRV
  • Ubiquitin

ASJC Scopus subject areas

  • General


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