KSHV reactivation and novel implications of protein isomerization on lytic switch control

Jonathan Guito, David Lukac

Research output: Contribution to journalReview article

18 Citations (Scopus)

Abstract

In Kaposi’s sarcoma-associated herpesvirus (KSHV) oncogenesis, both latency and reactivation are hypothesized to potentiate tumor growth. The KSHV Rta protein is the lytic switch for reactivation. Rta transactivates essential genes via interactions with cofactors such as the cellular RBP-Jk and Oct-1 proteins, and the viral Mta protein. Given that robust viral reactivation would facilitate antiviral responses and culminate in host cell lysis, regulation of Rta’s expression and function is a major determinant of the latent-lytic balance and the fate of infected cells. Our lab recently showed that Rta transactivation requires the cellular peptidyl-prolyl cis/trans isomerase Pin1. Our data suggest that proline-directed phosphorylation regulates Rta by licensing binding to Pin1. Despite Pin1’s ability to stimulate Rta transactivation, unchecked Pin1 activity inhibited virus production. Dysregulation of Pin1 is implicated in human cancers, and KSHV is the latest virus known to co-opt Pin1 function. We propose that Pin1 is a molecular timer that can regulate the balance between viral lytic gene expression and host cell lysis. Intriguing scenarios for Pin1’s underlying activities, and the potential broader significance for isomerization of Rta and reactivation, are highlighted.

Original languageEnglish (US)
Pages (from-to)72-109
Number of pages38
JournalViruses
Volume7
Issue number1
DOIs
StatePublished - Jan 12 2015

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Human Herpesvirus 8
Transcriptional Activation
Octamer Transcription Factors
Viruses
Proteins
Viral Genes
Essential Genes
Viral Proteins
Licensure
Proline
Antiviral Agents
Neoplasms
Carcinogenesis
Phosphorylation
Gene Expression
Growth

All Science Journal Classification (ASJC) codes

  • Infectious Diseases
  • Virology

Cite this

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abstract = "In Kaposi’s sarcoma-associated herpesvirus (KSHV) oncogenesis, both latency and reactivation are hypothesized to potentiate tumor growth. The KSHV Rta protein is the lytic switch for reactivation. Rta transactivates essential genes via interactions with cofactors such as the cellular RBP-Jk and Oct-1 proteins, and the viral Mta protein. Given that robust viral reactivation would facilitate antiviral responses and culminate in host cell lysis, regulation of Rta’s expression and function is a major determinant of the latent-lytic balance and the fate of infected cells. Our lab recently showed that Rta transactivation requires the cellular peptidyl-prolyl cis/trans isomerase Pin1. Our data suggest that proline-directed phosphorylation regulates Rta by licensing binding to Pin1. Despite Pin1’s ability to stimulate Rta transactivation, unchecked Pin1 activity inhibited virus production. Dysregulation of Pin1 is implicated in human cancers, and KSHV is the latest virus known to co-opt Pin1 function. We propose that Pin1 is a molecular timer that can regulate the balance between viral lytic gene expression and host cell lysis. Intriguing scenarios for Pin1’s underlying activities, and the potential broader significance for isomerization of Rta and reactivation, are highlighted.",
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KSHV reactivation and novel implications of protein isomerization on lytic switch control. / Guito, Jonathan; Lukac, David.

In: Viruses, Vol. 7, No. 1, 12.01.2015, p. 72-109.

Research output: Contribution to journalReview article

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