Kruppel-associated box domain-associated protein-1 as a latency regulator for Kaposi's sarcoma-associated herpesvirus and its modulation by the viral protein kinase

Pei Ching Chang, Latricia D. Fitzgerald, Albert Van Geelen, Yoshihiro Izumiya, Thomas J. Ellison, Don Hong Wang, David K. Ann, Paul A. Luciw, Hsing Jien Kung

Research output: Contribution to journalArticle

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Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, a major AIDS-associated malignancy, and to hematologic malignancies, including primary effusion lymphoma and multicentric Castleman's disease. Like other herpesviruses, KSHV is capable of both latent and lytic replication. Understanding the molecular details associated with this transition from latency to lytic replication is key to controlling virus spread and can affect the development of intervention strategies. Here, we report that Kruppel-associated box domain-associated protein-1 (KAP-1)/ transcriptional intermediary factor 1β, a cellular transcriptional repressor that controls chromosomal remodeling, participates in the process of switching viral latency to lytic replication. Knockdown of KAP-1 by small interfering RNA leads to KSHV reactivation mediated by K-Rta, a key transcriptional regulator. In cells harboring latent KSHV, KAP-1 was associated with the majority of viral lytic-gene promoters. K-Rta overexpression induced the viral lytic cycle with concomitant reduction of KAP-1 binding to viral promoters. Association of KAP-1 with heterochromatin was modulated by both sumoylation and phoshorylation. During lytic replication of KSHV, KAP-1 was phosphorylated at Ser824. Several lines of evidence directly linked the viral protein kinase to this post-translational modification. Additional studies showed that this phosphorylation of KAP-1 produced a decrease in its sumoylation, consequently decreasing the ability of KAP-1 to condense chromatin on viral promoters. In summary, the cellular transcriptional repressor KAP-1 plays a role in regulating KSHV latency, and viral protein kinase modulates the chromatin remodeling function of this repressor.

Original languageEnglish
Pages (from-to)5681-5689
Number of pages9
JournalCancer Research
Volume69
Issue number14
DOIs
Publication statusPublished - Jul 15 2009
Externally publishedYes

Fingerprint

Human Herpesvirus 8
Viral Proteins
Protein Kinases
Sumoylation
Primary Effusion Lymphoma
Virus Latency
Chromatin Assembly and Disassembly
Viral Genes
Heterochromatin
Kaposi's Sarcoma
Herpesviridae
Hematologic Neoplasms
Post Translational Protein Processing
Small Interfering RNA
Chromatin
Protein Domains
Acquired Immunodeficiency Syndrome
Phosphorylation
Viruses
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kruppel-associated box domain-associated protein-1 as a latency regulator for Kaposi's sarcoma-associated herpesvirus and its modulation by the viral protein kinase. / Chang, Pei Ching; Fitzgerald, Latricia D.; Van Geelen, Albert; Izumiya, Yoshihiro; Ellison, Thomas J.; Wang, Don Hong; Ann, David K.; Luciw, Paul A.; Kung, Hsing Jien.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5681-5689.

Research output: Contribution to journalArticle

Chang, Pei Ching ; Fitzgerald, Latricia D. ; Van Geelen, Albert ; Izumiya, Yoshihiro ; Ellison, Thomas J. ; Wang, Don Hong ; Ann, David K. ; Luciw, Paul A. ; Kung, Hsing Jien. / Kruppel-associated box domain-associated protein-1 as a latency regulator for Kaposi's sarcoma-associated herpesvirus and its modulation by the viral protein kinase. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5681-5689.
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AU - Chang, Pei Ching

AU - Fitzgerald, Latricia D.

AU - Van Geelen, Albert

AU - Izumiya, Yoshihiro

AU - Ellison, Thomas J.

AU - Wang, Don Hong

AU - Ann, David K.

AU - Luciw, Paul A.

AU - Kung, Hsing Jien

PY - 2009/7/15

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AB - Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, a major AIDS-associated malignancy, and to hematologic malignancies, including primary effusion lymphoma and multicentric Castleman's disease. Like other herpesviruses, KSHV is capable of both latent and lytic replication. Understanding the molecular details associated with this transition from latency to lytic replication is key to controlling virus spread and can affect the development of intervention strategies. Here, we report that Kruppel-associated box domain-associated protein-1 (KAP-1)/ transcriptional intermediary factor 1β, a cellular transcriptional repressor that controls chromosomal remodeling, participates in the process of switching viral latency to lytic replication. Knockdown of KAP-1 by small interfering RNA leads to KSHV reactivation mediated by K-Rta, a key transcriptional regulator. In cells harboring latent KSHV, KAP-1 was associated with the majority of viral lytic-gene promoters. K-Rta overexpression induced the viral lytic cycle with concomitant reduction of KAP-1 binding to viral promoters. Association of KAP-1 with heterochromatin was modulated by both sumoylation and phoshorylation. During lytic replication of KSHV, KAP-1 was phosphorylated at Ser824. Several lines of evidence directly linked the viral protein kinase to this post-translational modification. Additional studies showed that this phosphorylation of KAP-1 produced a decrease in its sumoylation, consequently decreasing the ability of KAP-1 to condense chromatin on viral promoters. In summary, the cellular transcriptional repressor KAP-1 plays a role in regulating KSHV latency, and viral protein kinase modulates the chromatin remodeling function of this repressor.

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