Nucleolar stress enhances lytic reactivation of the Kaposi's sarcoma-associated herpesvirus

Anastasia Gelgor, Chen Gam ze Letova, Yana Yegorov, Inna Kalt, Ronit Sarid

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumorigenic virus exhibiting two forms of infection, latent and lytic. Latent infection is abortive and allows the virus to establish lifelong infection, while lytic infection is productive, and is needed for virus dissemination within the host and between hosts. Latent infection may reactivate and switch towards the lytic cycle. This switch is a critical step in the maintenance of long-term infection and for the development of KSHV-related neoplasms. In this study, we examined the effect of nucleolar stress, manifested by failure in ribosome biogenesis or function and often coupled with p53 activation, on lytic reactivation of KSHV. To this end, we induced nucleolar stress by treatment with Actinomycin D, CX-5461 or BMH-21. Treatment with these compounds alone did not induce the lytic cycle. However, enhancement of the lytic cycle by these compounds was evident when combined with expression of the viral protein K-Rta. Further experiments employing combined treatments with Nutlin-3, knock-down of p53 and isogenic p53+/+ and p53-/- cells indicated that the enhancement of lytic reactivation by nucleolar stress does not depend on p53. Thus, our study identifies nucleolar stress as a novel regulator of KSHV infection, which synergizes with K-Rta expression to increase lytic reactivation. This suggests that certain therapeutic interventions, which induce nucleolar stress, may affect the outcome of KSHV infection.

Original languageEnglish
Pages (from-to)13822-13833
Number of pages12
JournalOncotarget
Volume9
Issue number17
DOIs
StatePublished - 2 Mar 2018

Bibliographical note

Publisher Copyright:
© Gelgor et al.

Keywords

  • KSHV
  • Kaposi's sarcoma-associated herpesvirus
  • Lytic reactivation
  • Nucleolar stress
  • P53

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