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

TY - JOUR

T1 - KSHV reactivation and novel implications of protein isomerization on lytic switch control

AU - Guito, Jonathan

AU - Lukac, David M.

N1 - Publisher Copyright: © 2015 by the authors; licensee MDPI, Basel, Switzerland.

PY - 2015/1/12

Y1 - 2015/1/12

N2 - 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.

AB - 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.

KW - Herpesvirus

KW - Human herpesvirus-8

KW - Kaposi’s sarcoma-associated herpesvirus

KW - Peptidyl-prolyl cis/trans isomerase

KW - Pin1

KW - Reactivation

KW - Rta

KW - Transcriptional activation

UR - http://www.scopus.com/inward/record.url?scp=84921290772&partnerID=8YFLogxK

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U2 - https://doi.org/10.3390/v7010072

DO - https://doi.org/10.3390/v7010072

M3 - Review article

C2 - 25588053

SN - 1999-4915

VL - 7

SP - 72

EP - 109

JO - Viruses

JF - Viruses

IS - 1

ER -