Kaposi's Sarcoma-Associated Herpesvirus K-Rta Exhibits SUMO-Targeting Ubiquitin Ligase (STUbL) Like Activity and Is Essential for Viral Reactivation

Yoshihiro Izumiya, Keisuke Kobayashi, Kevin Y. Kim, Mamata Pochampalli, Chie Izumiya, Bogdan Shevchenko, Don Hong Wang, Steve B. Huerta, Anthony Martinez, Mel Campbell, Hsing Jien Kung

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rta's ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene regulatory programs.

Original languageEnglish
Article numbere1003506
JournalPLoS Pathogens
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 1 2013
Externally publishedYes

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Human Herpesvirus 8
Ligases
Ubiquitin
Leukemia
Sumoylation
Viruses
Herpesviridae Infections
Protein Array Analysis
Mutation
Herpesviridae
Viral Proteins
Regulator Genes
Virus Replication

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Kaposi's Sarcoma-Associated Herpesvirus K-Rta Exhibits SUMO-Targeting Ubiquitin Ligase (STUbL) Like Activity and Is Essential for Viral Reactivation. / Izumiya, Yoshihiro; Kobayashi, Keisuke; Kim, Kevin Y.; Pochampalli, Mamata; Izumiya, Chie; Shevchenko, Bogdan; Wang, Don Hong; Huerta, Steve B.; Martinez, Anthony; Campbell, Mel; Kung, Hsing Jien.

In: PLoS Pathogens, Vol. 9, No. 8, e1003506, 01.08.2013.

Research output: Contribution to journalArticle

Izumiya, Y, Kobayashi, K, Kim, KY, Pochampalli, M, Izumiya, C, Shevchenko, B, Wang, DH, Huerta, SB, Martinez, A, Campbell, M & Kung, HJ 2013, 'Kaposi's Sarcoma-Associated Herpesvirus K-Rta Exhibits SUMO-Targeting Ubiquitin Ligase (STUbL) Like Activity and Is Essential for Viral Reactivation', PLoS Pathogens, vol. 9, no. 8, e1003506. https://doi.org/10.1371/journal.ppat.1003506
Izumiya, Yoshihiro ; Kobayashi, Keisuke ; Kim, Kevin Y. ; Pochampalli, Mamata ; Izumiya, Chie ; Shevchenko, Bogdan ; Wang, Don Hong ; Huerta, Steve B. ; Martinez, Anthony ; Campbell, Mel ; Kung, Hsing Jien. / Kaposi's Sarcoma-Associated Herpesvirus K-Rta Exhibits SUMO-Targeting Ubiquitin Ligase (STUbL) Like Activity and Is Essential for Viral Reactivation. In: PLoS Pathogens. 2013 ; Vol. 9, No. 8.
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