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The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication

RSK1, an essential cellular kinase for Kaposi’s sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attachi...

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Autores principales: Liu, Zhenshan, Wang, Xin, Liu, Chengrong, Deng, Hongying, Li, Wenshu, Wang, Xiaoqian, Xu, Xue, Xiao, Maggie Z. X., Wang, Chunxia, Zhang, Yucai, Fu, Joyce, Zhu, Fanxiu, Liang, Qiming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089915/
https://www.ncbi.nlm.nih.gov/pubmed/35482828
http://dx.doi.org/10.1371/journal.ppat.1010504
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author Liu, Zhenshan
Wang, Xin
Liu, Chengrong
Deng, Hongying
Li, Wenshu
Wang, Xiaoqian
Xu, Xue
Xiao, Maggie Z. X.
Wang, Chunxia
Zhang, Yucai
Fu, Joyce
Zhu, Fanxiu
Liang, Qiming
author_facet Liu, Zhenshan
Wang, Xin
Liu, Chengrong
Deng, Hongying
Li, Wenshu
Wang, Xiaoqian
Xu, Xue
Xiao, Maggie Z. X.
Wang, Chunxia
Zhang, Yucai
Fu, Joyce
Zhu, Fanxiu
Liang, Qiming
author_sort Liu, Zhenshan
collection PubMed
description RSK1, an essential cellular kinase for Kaposi’s sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attaching SUMO to RSK1 has not yet been identified. By genome-wide screening, we found that KSHV ORF45 is necessary and sufficient to enhance RSK1 SUMOylation. Mechanistically, KSHV ORF45 binds to SUMOs via two classic SUMO-interacting motifs (SIMs) and functions as a SIM-dependent SUMO E3 ligase for RSK1. Mutations on these ORF45 SIMs resulted in much lower lytic gene expressions, viral DNA replication, and mature progeny virus production. Interestingly, KSHV ORF45 controls RSK1 SUMOylation and phosphorylation via two separated functional regions: SIMs and amino acid 17–90, respectively, which do not affect each other. Similar to KSHV ORF45, ORF45 of Rhesus Macaque Rhadinovirus has only one SIM and also increases RSK1 SUMOylation in a SIM-dependent manner, while other ORF45 homologues do not have this function. Our work characterized ORF45 as a novel virus encoded SUMO E3 ligase, which is required for ORF45-RSK1 axis-mediated KSHV lytic gene expression.
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spelling pubmed-90899152022-05-11 The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication Liu, Zhenshan Wang, Xin Liu, Chengrong Deng, Hongying Li, Wenshu Wang, Xiaoqian Xu, Xue Xiao, Maggie Z. X. Wang, Chunxia Zhang, Yucai Fu, Joyce Zhu, Fanxiu Liang, Qiming PLoS Pathog Research Article RSK1, an essential cellular kinase for Kaposi’s sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attaching SUMO to RSK1 has not yet been identified. By genome-wide screening, we found that KSHV ORF45 is necessary and sufficient to enhance RSK1 SUMOylation. Mechanistically, KSHV ORF45 binds to SUMOs via two classic SUMO-interacting motifs (SIMs) and functions as a SIM-dependent SUMO E3 ligase for RSK1. Mutations on these ORF45 SIMs resulted in much lower lytic gene expressions, viral DNA replication, and mature progeny virus production. Interestingly, KSHV ORF45 controls RSK1 SUMOylation and phosphorylation via two separated functional regions: SIMs and amino acid 17–90, respectively, which do not affect each other. Similar to KSHV ORF45, ORF45 of Rhesus Macaque Rhadinovirus has only one SIM and also increases RSK1 SUMOylation in a SIM-dependent manner, while other ORF45 homologues do not have this function. Our work characterized ORF45 as a novel virus encoded SUMO E3 ligase, which is required for ORF45-RSK1 axis-mediated KSHV lytic gene expression. Public Library of Science 2022-04-28 /pmc/articles/PMC9089915/ /pubmed/35482828 http://dx.doi.org/10.1371/journal.ppat.1010504 Text en © 2022 Liu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liu, Zhenshan
Wang, Xin
Liu, Chengrong
Deng, Hongying
Li, Wenshu
Wang, Xiaoqian
Xu, Xue
Xiao, Maggie Z. X.
Wang, Chunxia
Zhang, Yucai
Fu, Joyce
Zhu, Fanxiu
Liang, Qiming
The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication
title The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication
title_full The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication
title_fullStr The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication
title_full_unstemmed The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication
title_short The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication
title_sort sumo e3 ligase activity of orf45 determines kshv lytic replication
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089915/
https://www.ncbi.nlm.nih.gov/pubmed/35482828
http://dx.doi.org/10.1371/journal.ppat.1010504
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