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The Epstein-Barr Virus Oncoprotein, LMP1, Regulates the Function of SENP2, a SUMO-protease.


ABSTRACT: Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) activates numerous signal transduction pathways using its C-terminal activating regions. We reported that LMP1 increased global levels of sumoylated proteins, which aided the oncogenic nature of LMP1. Because increased protein sumoylation is detected in numerous cancers, we wanted to elucidate additional mechanisms by which LMP1 modulates the sumoylation machinery. Results indicated that SUMO-protease activity decreased in a LMP1-dependent manner, so we hypothesized that LMP1 inhibits SUMO-protease activity, resulting in reduced de-sumoylation of cellular proteins, which contributes to the detected accumulation of sumoylated proteins in EBV-positive lymphomas. Focusing on SENP2, findings revealed that LMP1 expression corresponded with increased sumoylation of SENP2 at K48 and K447 in a CTAR-dependent manner. Interestingly, independent of LMP1-induced sumoylation of SENP2, LMP1 also decreased SENP2 activity, decreased SENP2 turnover, and altered the localization of SENP2, which led us to investigate if LMP1 regulated the biology of SENP2 by a different post-translational modification, specifically ubiquitination. Data showed that expression of LMP1 inhibited the ubiquitination of SENP2, and inhibition of ubiquitination was sufficient to mimic LMP1-induced changes in SENP2 activity and trafficking. Together, these findings suggest that LMP1 modulates different post-translational modifications of SENP2 in order to modulate its biology and identify a third member of the sumoylation machinery that is manipulated by LMP1 during latent EBV infections, which can affect oncogenesis.

SUBMITTER: Selby TL 

PROVIDER: S-EPMC6606635 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The Epstein-Barr Virus Oncoprotein, LMP1, Regulates the Function of SENP2, a SUMO-protease.

Selby Thomas L TL   Biel Natalie N   Varn Matthew M   Patel Sheetal S   Patel Akash A   Hilding Leslie L   Ray Ashley A   Ross Tabithia T   Cramblet Wyatt T WT   Moss C Randall CR   Lowrey Angela J AJ   Bentz Gretchen L GL  

Scientific reports 20190702 1


Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) activates numerous signal transduction pathways using its C-terminal activating regions. We reported that LMP1 increased global levels of sumoylated proteins, which aided the oncogenic nature of LMP1. Because increased protein sumoylation is detected in numerous cancers, we wanted to elucidate additional mechanisms by which LMP1 modulates the sumoylation machinery. Results indicated that SUMO-protease activity decreased in a LMP1-dependen  ...[more]

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