RSK1 SUMOylation is required for KSHV lytic replication.
RSK1 SUMOylation is required for KSHV lytic replication.
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KSHV 裂解复制需要 RSK1 SUMOylation
DOI：
10.1371/journal.ppat.1010123
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发表时间：
2021-12
期刊：
影响因子：
6.7
通讯作者：
Liang Q
中科院分区：
文献类型：
--
作者：
Liu Z;Liu C;Wang X;Li W;Zhou J;Dong P;Xiao MZX;Wang C;Zhang Y;Fu J;Zhu F;Liang Q
RSK1是MAPK途径下游的一种激酶，它调节多种细胞过程，对包括卡波西肉瘤相关疱疹病毒(KSHV)在内的多种病毒的裂解复制是必不可少的。除了磷酸化，目前还不清楚其他翻译后修饰是否在调节RSK1功能方面发挥重要作用。我们证明，在KSHV裂解复制过程中，RSK1在赖氨酸残基K110、K335和K421处经历了强有力的SUMO化。相扑修饰不改变KSHV ORF45共表达时RSK1的激活和蛋白激酶活性，但影响RSK1下游底物的磷酸化。与野生型RSK1相比，RSK1K110/335/421R表达细胞中RxRxxS*/T*基序的整体磷酸化水平显著降低。具体地说，糖基化缺陷的RSK1不能有效地磷酸化eIF4B。序列分析表明，eIF4B在第166和170位氨基酸之间有一个相扑相互作用基序(SIM)，它通过相扑-SIM相互作用介导eIF4B与RSK1之间的相互作用。这些结果表明，SUMO化调节RSK1下游底物的磷酸化，这是有效的KSHV裂解复制所必需的。RSK1是卡波西肉瘤相关疱疹病毒(KSHV)裂解复制所必需的细胞激酶。除了磷酸化，目前还不清楚其他翻译后修饰是否在调节RSK1功能方面发挥重要作用。在这里，我们发现RSK1在赖氨酸残基K110、K335和K421处发生SUMO化，这一点被KSHV裂解复制增强。有效的KSHV裂解复制需要RSK1的SUMO化，其SUMO化位点上的突变会导致裂解基因表达减少，并损害后代病毒的生产。有趣的是，相扑修饰并不改变KSHV ORF45共表达时RSK1的激活和激酶活性，但影响RSK1下游底物的磷酸化。具体地说，SUMO化缺陷的RSK1不能有效地磷酸化eIF4B，因为SUMO-SIM相互作用介导了eIF4B和RSK1之间的联系。这些结果表明，SUMO化调节RSK1下游底物的磷酸化，这是有效的KSHV裂解复制所必需的。
RSK1, a downstream kinase of the MAPK pathway, has been shown to regulate multiple cellular processes and is essential for lytic replication of a variety of viruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV). Besides phosphorylation, it is not known whether other post-translational modifications play an important role in regulating RSK1 function. We demonstrate that RSK1 undergoes robust SUMOylation during KSHV lytic replication at lysine residues K110, K335, and K421. SUMO modification does not alter RSK1 activation and kinase activity upon KSHV ORF45 co-expression, but affects RSK1 downstream substrate phosphorylation. Compared to wild-type RSK1, the overall phosphorylation level of RxRxxS*/T* motif is significantly declined in RSK1K110/335/421R expressing cells. Specifically, SUMOylation deficient RSK1 cannot efficiently phosphorylate eIF4B. Sequence analysis showed that eIF4B has one SUMO-interacting motif (SIM) between the amino acid position 166 and 170 (166IRVDV170), which mediates the association between eIF4B and RSK1 through SUMO-SIM interaction. These results indicate that SUMOylation regulates the phosphorylation of RSK1 downstream substrates, which is required for efficient KSHV lytic replication. RSK1 is an essential celluar kinase for lytic replication of Kaposi’s sarcoma-associated herpesvirus (KSHV). Besides phosphorylation, it is not known whether other post-translational modifications play an important role in regulating RSK1 function. Here, we found that RSK1 is SUMOylated at lysine residues K110, K335, and K421, which is enhanced by KSHV lytic replication. RSK1 SUMOylation is required for effient KSHV lytic replication and mutations on its SUMOylation sites leads to reduced lytic gene expressions and impaired progeny virus production. Interestingly, SUMO modification does not alter RSK1 activation and kinase activity upon KSHV ORF45 co-expression, but affects RSK1 downstream substrate phosphorylation. Specifically, SUMOylation deficient RSK1 cannot efficiently phosphorylate eIF4B since SUMO-SIM interaction mediates the association between eIF4B and RSK1. These results indicate that SUMOylation regulates the phosphorylation of RSK1 downstream substrates, which is required for efficient KSHV lytic replication.
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