Epstein-Barr Virus (EBV) is well known to manipulate the host ubiquitin machinery to facilitate its latent persistence and oncogenesis, exemplified by LMP1 signal transduction that activates multiple transcription factors, including NFκB, AP1, and IRF7/IRF4, which promote cell survival and outgrowth, and control immune response and inflammation. It is therefore vital to delineate the detailed mechanisms underlying LMP1 signal transduction for understanding EBV-mediated oncogenesis. p62 (also called SQSTM1, Sequestosome 1) is a ubiquitin sensor and a signal transducing adaptor that interacts with TRAF6 and facilitates the recruitment of ubiquitinated signal intermediators for the activation of NFκB and AP1 in diverse contexts. In turn, p62 is induced by NFκB. However, the interaction between p62 and EBV latency has never been studied. We have recently published interesting and important results, which imply a crucial role for p62 in EBV-mediated oxidative stress. In this study, we further show that p62 is upregulated in EBV latency, with the contribution of LMP1-mediated NFκB and AP1 activities. In turn, p62 participates in LMP1 signal transduction through its interaction with TRAF6, promoting TRAF6 ubiquitination. shRNA-mediated p62 depletion downregulates LMP1-TRAF6 interaction and TRAF6 ubiquitination, and significantly impairs AP1 activity; however, with no detectable effects on NFκB activity. These observations imply that TRAF6-p62 interaction differentiates LMP1 signaling to NFκB and AP1 activation. As a consequence, p62 depletion promotes etoposide-induced apoptosis. These findings identify p62 as a novel player in EBV LMP1 signaling to AP1 activation that is crucial for LMP1-mediated ROS production.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:asrf-1515 |
| Date | 04 May 2020 |
| Creators | Sparks-Wallace, Ayrianna, Ning, Shunbin |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Appalachian Student Research Forum |
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