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

Abstract

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.

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

“…Overexpression of TRIM5a reduces the transactivating capabilities of Rta, whereas reducing TRIM5a expression enhances EBV lytic protein levels and DNA replication. 175 …”

“…Overexpression of TRIM5a reduces the transactivating capabilities of Rta, whereas reducing TRIM5a expression enhances EBV lytic protein levels and DNA replication. 175 Besides utilizing host DUBs, EBV can also encode the viral deubiquitinating enzyme (v-DUB), BPLF1, which is an immune evasion gene product that can suppress antiviral immune responses during primary infection. BPLF1 is expressed during the late phase of lytic EBV infection and is incorporated into viral particles.…”

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

“…Herpesviruses are also susceptible to TRIM5α, with the replication and transcription activator (Rta) from Epstein-Barr virus (EBV) as an identified target [74]. MS screening of host factors that interact with Rta identified TRIM5α and further characterization revealed that both factors interact in the nucleus [74]. Rta functions during the immediate-early stage of EBV infection and facilitates the transcription of EBV lytic genes that initiate progeny virion formation and release [74].…”

“…MS screening of host factors that interact with Rta identified TRIM5α and further characterization revealed that both factors interact in the nucleus [74]. Rta functions during the immediate-early stage of EBV infection and facilitates the transcription of EBV lytic genes that initiate progeny virion formation and release [74]. This process is subdued by TRIM5α through Rta targeting for ubiquitination and proteasomal degradation, suggesting nuclear TRIM5α maintains EBV latency in infected cells [74].…”

The TRIMendous Role of TRIMs in Virus–Host Interactions

“…Epstein–Barr virus (EBV) replication and transcription activator (Rta) protein activates EBV lytic genes for proliferation [ 238 ]. TRIM5α promotes the ubiquitination of Rta upon interaction, thereby blocking the EBV lytic cycle [ 238 ]. The involvement of TRIM5α in a non-retroviral innate immune response implies TRIMs possess diverse, situation-specific functions that have yet to be characterized.…”