Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO E3 ligase that is SIM-dependent and SUMO-2/3-specific.
Sumoylation has emerged as a major post-translational modification of cellular proteins, affecting a variety of cellular processes. Viruses have exploited the sumoylation pathway to advance their own replication by evolving several ways to perturb the host sumoylation apparatus. However, there has been no report of virally encoded enzymes directly involved in catalyzing the sumoylation reaction. Here, we report that the K-bZIP protein encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) is a SUMO E3 ligase with specificity toward SUMO2/3. K-bZIP is a nuclear factor that functions to modulate viral gene expression and to prolong the G1 phase, allowing viral transcription and translation to proceed at the early stage of infection. In addition to functioning as a transcriptional factor, we show that K-bZIP carries a SIM (SUMO-interacting motif), which specifically binds to SUMO-2/3 but not SUMO-1. K-bZIP catalyzes its own SUMO modification as well as that of its interacting partners such as the cellular tumor suppressor proteins p53 and Rb, both in vitro and in vivo. This reaction depends on an intact SIM. Sumoylation of p53 leads to its activation and K-bZIP is recruited to several p53 target chromatin sites in a SIM-dependent manner. In addition to the identification of a viral SUMO-2/3 E3 ligase, our results provide additional insights into the mechanisms whereby K-bZIP induces cell cycle arrest.
Chang
Pei-Ching
PC
Department of Biological Chemistry and Molecular Medicine, University of California, Davis, California 95616, USA.
Izumiya
Yoshihiro
Y
Wu
Chun-Yi
CY
Fitzgerald
Latricia D
LD
Campbell
Mel
M
Ellison
Thomas J
TJ
Lam
Kit S
KS
Luciw
Paul A
PA
Kung
Hsing-Jien
HJ
D020816:Amino Acid Motifs / Q000502:physiology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016193:G1 Phase / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D011499:Protein Processing, Post-Translational / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; C118265:K8 protein, Human herpesvirus 8; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases