Abstract
Ubiquitination and deubiquitination of cellular proteins are reciprocal reactions catalyzed by ubiquitination-related enzymes and deubiquitinase (DUB) which regulate almost all cellular processes. Marek’s disease virus (MDV) encodes a viral DUB that plays an important role in the MDV pathogenicity. Chicken CD4+ T-cell lymphoma induced by MDV is a key contributor to multiple visceral tumors and immunosuppression of chickens with Marek’s disease (MD). However, alterations in the ubiquitylome of MDV-induced T lymphoma cells are still unclear. In this study, a specific antibody against K-ε-GG was used to isolate ubiquitinated peptides from CD4+ T cells and MD T lymphoma cells. Mass spectrometry was used to compare and analyze alterations in the ubiquitylome. Our results showed that the ubiquitination of 717 and 778 proteins was significantly up- and downregulated, respectively, in T lymphoma cells. MDV up- and downregulated ubiquitination of a similar percentage of proteins. The ubiquitination of transferases, especially serine/threonine kinases, was the main regulatory target of MDV. Compared with CD4+ T cells of the control group, MDV mainly altered the ubiquitylome associated with the signal transduction, immune system, cancer, and infectious disease pathways in T lymphoma cells. In these pathways, the ubiquitination of CDK1, IL-18, PRKCB, ETV6, and EST1 proteins was significantly up- or downregulated as shown by immunoblotting. The current study revealed that the MDV infection could exert a significant influence on the ubiquitylome of CD4+ T cells.
Highlights
Marek’s disease (MD) is an avian oncogenic lymphoproliferative infectious disease induced by the serotype 1 Marek’s disease virus (MDV-1) [1]
Compared to purified CD4+ T cells, it was found that MDV-encoded DUB, UL36, is highly expressed in MD T lymphoma cells (Figures S1 and S2)
The complete list of proteins with significantly up- and downregulated ubiquitination detected in the T lymphoma cells is given in the Table S1
Summary
Marek’s disease (MD) is an avian oncogenic lymphoproliferative infectious disease induced by the serotype 1 Marek’s disease virus (MDV-1) [1]. An MD-induced tumor was the first viral tumor successfully controlled by vaccination [3], and the CVI-988 vaccine, an attenuated MDV serotype 1 strain, is the most effective vaccine against MD in poultry. T cells, especially CD4+ T cells, are susceptible to infection and transformation by MDV [1] This subsequently leads to the development of T lymphomas in peripheral nerves and visceral organs, which induces immunosuppression in MD chickens [1]. HSV-1 encoded E3 ligase ICP0 and DUB UL36, UL36 of MDV, UL48 of HCMV, Orf of KSHV, and BPLF1 of EBV [20] Viruses utilize these products to hijack the cellular ubiquitination regulatory machinery to promote viral infection, replication, pathogenicity, and genome integration [20]. The ubiquitination-related alterations of some proteins were verified by immunoblotting
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