Role of RNF4 in the Ubiquitination of Rta of Epstein-Barr Virus

Yang, Ya Chun; Yoshikai, Yushi; Hsu, Shih Wei; Saitoh, Hisato; Chang, Li

doi:10.1074/jbc.m112.413393

Cited by 30 publications

(36 citation statements)

References 82 publications

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“…Recent studies have indicated an important role for RNF4 or RNF4-like proteins in several cellular functions, including ATO-induced degradation of SUMOylated promyelocytic leukemia protein (PML) (31,34,35), phorbol 12-myristate 13-acetate (PMA)/MAPK-stimulated degradation of SUMOylated polyomavirus enhancer activator 3 (PEA3) (43), heat shock-triggered degradation of SUMOylated poly(ADP-ribose) polymerase 1 (PARP-1) (44), hypoxia-activated degradation of SUMOylated hypoxia-inducible factor 2␣ (HIF-2␣) (45), and degradation of SUMOylated Rta viral transcription factor during the lytic cycle of EBV (46). Moreover, Kaposi sarcoma-associated herpesvirus K-Rta resembles RNF4 to degrade SUMOylated PML nuclear bodies against host immune response and to facilitate viral reactivation (47).…”

Section: Discussionmentioning

confidence: 99%

An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Krüppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress

Kuo

Kong

et al. 2014

Journal of Biological Chemistry

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Background:The function of KAP1 is regulated by multiple posttranslational modifications during DNA damage response. Results: A previously unidentified arginine-rich motif (ARM) of RNF4 regulates the phosphorylation-induced, SUMO-dependent recruitment and degradation of KAP1. Conclusion:The ARM of RNF4 enhances SIM-SUMO-dependent recruitment. Significance: The bimodular recognition by RNF4 could be critical for fine-tuning substrate selection during DNA damage response and other stress conditions.

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Section: Discussionmentioning

confidence: 99%

An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Krüppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress

Kuo

Kong

et al. 2014

Journal of Biological Chemistry

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“…Plasmids that express deletion mutants of GFP-Rta, including GFP-N190, GFP-N191/415, and GFP-Rev have been described previously (Hsu et al, 2005; Chang et al, 2010; Yang and Chang, 2013). Plasmids pFlag-Ub, pFlag-Rta, and pET-Rta, which express Flag-tagged ubiquitin, Flag-tagged Rta and His-tagged Rta, were described earlier (Yang et al, 2013). For transient transfection assays, the reporter plasmid, pBMRF1, was constructed by inserting a PCR-amplified DNA fragment containing the -172 to +20 region in BMRF1 into pGL2-Basic (Chang et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, we showed that Rta is conjugated to SUMO-1 by Ubc9 and PIAS (protein inhibitor of activated STAT) proteins, and this sumoylation enhances Rta transactivation activity (Chang et al, 2004). Rta is also modified by SUMO-2 (Heilmann et al, 2010), and can be ubiquitinated via the SUMO chain by a SUMO-targeted E3 ubiquitin ligase, RNF4, thereby inhibiting EBV lytic activation (Yang et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

TRIM5α Promotes Ubiquitination of Rta from Epstein–Barr Virus to Attenuate Lytic Progression

et al. 2017

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Replication and transcription activator (Rta), a key protein expressed by Epstein–Barr virus (EBV) during the immediate-early stage of the lytic cycle, is responsible for the activation of viral lytic genes. In this study, GST-pulldown and coimmunoprecipitation assays showed that Rta interacts in vitro and in vivo with TRIM5α, a host factor known to be involved in the restriction of retroviral infections. Confocal microscopy results revealed that Rta colocalizes with TRIM5α in the nucleus during lytic progression. The interaction involves 190 amino acids in the N-terminal of Rta and the RING domain in TRIM5α, and it was further found that TRIM5α acts as an E3 ubiquitin ligase to promote Rta ubiquitination. Overexpression of TRIM5α reduced the transactivating capabilities of Rta, while reducing TRIM5α expression enhanced EBV lytic protein expression and DNA replication. Taken together, these results point to a critical role for TRIM5α in attenuating EBV lytic progression through the targeting of Rta for ubiquitination, and suggest that the restrictive capabilities of TRIM5α may go beyond retroviral infections.

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“…A plasmid expressing ataxin-3-79Q-HA (pAtaxin3-79Q-HA) was obtained from Hung-Li Wang (51). A plasmid expressing GFP-RNF4 was reported earlier (52).…”

Section: Methodsmentioning

confidence: 99%

Assembly of Epstein-Barr Virus Capsid in Promyelocytic Leukemia Nuclear Bodies

Wang

Kuo

Chang

et al. 2015

J Virol

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The Epstein-Barr virus (EBV) capsid contains a major capsid protein, VCA; two minor capsid proteins, BDLF1 and BORF1; and a small capsid protein, BFRF3. During the lytic cycle, these capsid proteins are synthesized and imported into the host nucleus for capsid assembly. This study finds that EBV capsid proteins colocalize with promyelocytic leukemia (PML) nuclear bodies (NBs) in P3HR1 cells during the viral lytic cycle, appearing as nuclear speckles under a confocal laser scanning microscope. In a glutathione S-transferase pulldown study, we show that BORF1 interacts with PML-NBs in vitro. BORF1 also colocalizes with PML-NBs in EBV-negative Akata cells after transfection and is responsible for bringing VCA and the VCA-BFRF3 complex from the cytoplasm to PML-NBs in the nucleus. Furthermore, BDLF1 is dispersed throughout the cell when expressed alone but colocalizes with PML-NBs when BORF1 is also present in the cell. In addition, this study finds that knockdown of PML expression by short hairpin RNA does not influence the intracellular levels of capsid proteins but reduces the number of viral particles produced by P3HR1 cells. Together, these results demonstrate that BORF1 plays a critical role in bringing capsid proteins to PMLNBs, which may likely be the assembly sites of EBV capsids. The mechanisms elucidated in this study are critical to understanding the process of EBV capsid assembly. IMPORTANCECapsid assembly is an important event during the Epstein-Barr virus (EBV) lytic cycle, as this process is required for the production of virions. In this study, confocal microscopy revealed that the EBV capsid protein BORF1 interacts with promyelocytic leukemia (PML) nuclear bodies (NBs) in the host nucleus and is responsible for transporting the other EBV capsid proteins, including VCA, BDLF1, and BFRF3, to these subnuclear locations prior to initiation of capsid assembly. This study also found that knockdown of PML expression by short hairpin RNA significantly reduces EBV capsid assembly capabilities. This enhanced understanding of capsid assembly offers potential for the development of novel antiviral strategies and therapies that can prevent the propagation and spread of EBV.

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Role of RNF4 in the Ubiquitination of Rta of Epstein-Barr Virus

Cited by 30 publications

References 82 publications

An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Krüppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress

An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Krüppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress

TRIM5α Promotes Ubiquitination of Rta from Epstein–Barr Virus to Attenuate Lytic Progression

Assembly of Epstein-Barr Virus Capsid in Promyelocytic Leukemia Nuclear Bodies

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