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

Guito J, Lukac DM - Viruses (2015)

Bottom Line: In Kaposi's sarcoma-associated herpesvirus (KSHV) oncogenesis, both latency and reactivation are hypothesized to potentiate tumor growth.Dysregulation of Pin1 is implicated in human cancers, and KSHV is the latest virus known to co-opt Pin1 function.Intriguing scenarios for Pin1's underlying activities, and the potential broader significance for isomerization of Rta and reactivation, are highlighted.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School and Graduate School of Biomedical Sciences, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103, USA. ypw1@cdc.gov.

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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Related in: MedlinePlus

Rta protein is rich with conserved prolines. 17% of Rta’s conserved aa are prolines. At bottom are Rta primary sequence alignments of two proline-rich regions (A) and (B), denoted by yellow and green boxes, to the TAF50 γ-herpesvirinae superfamily. Numbers indicate aa position. +++ = positively-charged aa-rich, LR = leucine heptapeptide repeat domain, S/T = serine/threonine-rich, hyd DE hyd = hydrophobic/charged/hydrophobic aa-rich, NLS = nuclear localization signal sequence. Red lines mark putative phosphorylated residue sites; * = known phosphorylated residue. Figure modified from [166].
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viruses-07-00072-f004: Rta protein is rich with conserved prolines. 17% of Rta’s conserved aa are prolines. At bottom are Rta primary sequence alignments of two proline-rich regions (A) and (B), denoted by yellow and green boxes, to the TAF50 γ-herpesvirinae superfamily. Numbers indicate aa position. +++ = positively-charged aa-rich, LR = leucine heptapeptide repeat domain, S/T = serine/threonine-rich, hyd DE hyd = hydrophobic/charged/hydrophobic aa-rich, NLS = nuclear localization signal sequence. Red lines mark putative phosphorylated residue sites; * = known phosphorylated residue. Figure modified from [166].

Mentions: Recently, our lab investigated a putative interaction between KSHV Rta and PPIase Pin1 in the regulation of Rta-mediated lytic reactivation at multiple stages of the lytic cycle cascade. In silico alignment analysis of the transcription activation factor (TAF) 50 superfamily revealed that Rta homologs share a consensus of 134 amino acids (residues conserved between KSHV Rta and at least one additional member). Proline consists of 38 of these amino acids, accounting for 16.7% of all of Rta’s conserved residues (Figure 4) [40,166]. The high degree of conservation supported their putative functional significance. We reasoned that modification of prolines may regulate Rta’s efficiency in transactivating target genes, licensing viral DNA replication and interacting with protein partners—which could drive the latency-lytic cycle balance in favor of productive replication.


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

Guito J, Lukac DM - Viruses (2015)

Rta protein is rich with conserved prolines. 17% of Rta’s conserved aa are prolines. At bottom are Rta primary sequence alignments of two proline-rich regions (A) and (B), denoted by yellow and green boxes, to the TAF50 γ-herpesvirinae superfamily. Numbers indicate aa position. +++ = positively-charged aa-rich, LR = leucine heptapeptide repeat domain, S/T = serine/threonine-rich, hyd DE hyd = hydrophobic/charged/hydrophobic aa-rich, NLS = nuclear localization signal sequence. Red lines mark putative phosphorylated residue sites; * = known phosphorylated residue. Figure modified from [166].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306829&req=5

viruses-07-00072-f004: Rta protein is rich with conserved prolines. 17% of Rta’s conserved aa are prolines. At bottom are Rta primary sequence alignments of two proline-rich regions (A) and (B), denoted by yellow and green boxes, to the TAF50 γ-herpesvirinae superfamily. Numbers indicate aa position. +++ = positively-charged aa-rich, LR = leucine heptapeptide repeat domain, S/T = serine/threonine-rich, hyd DE hyd = hydrophobic/charged/hydrophobic aa-rich, NLS = nuclear localization signal sequence. Red lines mark putative phosphorylated residue sites; * = known phosphorylated residue. Figure modified from [166].
Mentions: Recently, our lab investigated a putative interaction between KSHV Rta and PPIase Pin1 in the regulation of Rta-mediated lytic reactivation at multiple stages of the lytic cycle cascade. In silico alignment analysis of the transcription activation factor (TAF) 50 superfamily revealed that Rta homologs share a consensus of 134 amino acids (residues conserved between KSHV Rta and at least one additional member). Proline consists of 38 of these amino acids, accounting for 16.7% of all of Rta’s conserved residues (Figure 4) [40,166]. The high degree of conservation supported their putative functional significance. We reasoned that modification of prolines may regulate Rta’s efficiency in transactivating target genes, licensing viral DNA replication and interacting with protein partners—which could drive the latency-lytic cycle balance in favor of productive replication.

Bottom Line: In Kaposi's sarcoma-associated herpesvirus (KSHV) oncogenesis, both latency and reactivation are hypothesized to potentiate tumor growth.Dysregulation of Pin1 is implicated in human cancers, and KSHV is the latest virus known to co-opt Pin1 function.Intriguing scenarios for Pin1's underlying activities, and the potential broader significance for isomerization of Rta and reactivation, are highlighted.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School and Graduate School of Biomedical Sciences, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103, USA. ypw1@cdc.gov.

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.

Show MeSH
Related in: MedlinePlus