Research Papers:

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

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

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Oncotarget. 2018; 9:13822-13833. https://doi.org/10.18632/oncotarget.24497

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Anastasia Gelgor1,*, Chen Gam ze Letova1,*, Yana Yegorov1, Inna Kalt1 and Ronit Sarid1

1The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar Ilan University, Ramat-Gan, Israel

*These authors have contributed equally to this work

Correspondence to:

Ronit Sarid, email: [email protected]

Keywords: Kaposi’s sarcoma-associated herpesvirus; KSHV; lytic reactivation; nucleolar stress; p53

Abbreviations: KSHV, Kaposi’s sarcoma-associated herpesvirus; K-Rta, KSHV replication and transcription activator; Actinomycin D, Act D; Doxycycline, Dox

Received: February 14, 2017    Accepted: February 01, 2018    Published: February 15, 2018


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.

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