Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2024-06-15 , DOI: 10.1038/s41418-024-01327-0 Qin Yan 1, 2, 3 , Jing Zhou 1, 2 , Yang Gu 1, 2 , Wenjing Huang 1, 2 , Mingpeng Ruan 1, 2 , Haoran Zhang 1, 2 , Tianjiao Wang 1, 2 , Pengjun Wei 1, 2 , Guochun Chen 3, 4 , Wan Li 1, 2, 3 , Chun Lu 1, 2, 3
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N4-acetylcytidine (ac4C), a conserved but recently rediscovered RNA modification on tRNAs, rRNAs and mRNAs, is catalyzed by N-acetyltransferase 10 (NAT10). Lysine acylation is a ubiquitous protein modification that controls protein functions. Our latest study demonstrates a NAT10-dependent ac4C modification, which occurs on the polyadenylated nuclear RNA (PAN) encoded by oncogenic DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV), can induce KSHV reactivation from latency and activate inflammasome. However, it remains unclear whether a novel lysine acylation occurs in NAT10 during KSHV reactivation and how this acylation of NAT10 regulates tRNAs ac4C modification. Here, we showed that NAT10 was lactylated by α-tubulin acetyltransferase 1 (ATAT1), as a writer at the critical domain, to exert RNA acetyltransferase function and thus increase the ac4C level of tRNASer-CGA-1-1. Mutagenesis at the ac4C site in tRNASer-CGA-1-1 inhibited its ac4C modifications, translation efficiency of viral lytic genes, and virion production. Mechanistically, KSHV PAN orchestrated NAT10 and ATAT1 to enhance NAT10 lactylation, resulting in tRNASer-CGA-1-1 ac4C modification, eventually boosting KSHV reactivation. Our findings reveal a novel post-translational modification in NAT10, as well as expand the understanding about tRNA-related ac4C modification during KSHV replication, which may be exploited to design therapeutic strategies for KSHV-related diseases.
中文翻译:
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NAT10 的乳酰化促进 tRNASer-CGA-1-1 上的 N4-乙酰胞苷修饰,从而促进致癌 DNA 病毒 KSHV 重新激活
N 4 -乙酰胞苷 (ac 4 C) 是一种保守但最近重新发现的 tRNA、rRNA 和 mRNA 上的 RNA 修饰,由N -乙酰转移酶 10 (NAT10) 催化。赖氨酸酰化是一种普遍存在的控制蛋白质功能的蛋白质修饰。我们的最新研究表明,NAT10 依赖性 ac 4 C 修饰发生在致癌 DNA 病毒卡波西肉瘤相关疱疹病毒 (KSHV) 编码的聚腺苷酸化核 RNA (PAN) 上,可以诱导 KSHV 从潜伏期重新激活并激活炎症小体。然而,目前尚不清楚 KSHV 重新激活期间 NAT10 中是否发生新的赖氨酸酰化,以及 NAT10 的这种酰化如何调节 tRNA ac 4 C 修饰。在这里,我们发现 NAT10 作为关键域的写入者被 α-微管蛋白乙酰转移酶 1 (ATAT1) 乳酰化,发挥 RNA 乙酰转移酶功能,从而提高 tRNA Ser-CGA-1-1的 ac 4 C 水平。 tRNA Ser-CGA-1-1中 ac 4 C 位点的诱变抑制了其 ac 4 C 修饰、病毒裂解基因的翻译效率和病毒颗粒的产生。从机制上讲,KSHV PAN 协调 NAT10 和 ATAT1 以增强 NAT10 乳酰化,导致 tRNA Ser-CGA-1-1 ac 4 C 修饰,最终促进 KSHV 重新激活。我们的研究结果揭示了 NAT10 中的一种新的翻译后修饰,并扩大了对 KSHV 复制过程中 tRNA 相关的 ac 4 C 修饰的理解,这可用于设计 KSHV 相关疾病的治疗策略。