SERBP1 deacetylation inhibits ferroptosis to promote KSHV-induced cellular transformation by decaying lipoyltransferase 2 mRNA

Ferroptosis, a defensive strategy employed by the host to restrict pathogenic infections, has been implicated in the development and therapeutic responses of various types of tumors. However, the role of ferroptosis in KSHV-induced malignant tumors remains elusive. A steadily growing number of non-histone proteins have been identified as acetylation targets, their functions have yet to be revealed. In this study, we obtained a marked disparity in the landscape of acetylation between MM and KSHV-transformed MM (KMM) cells. SERBP1 deacetylation was upregulated in KMM cells and contributed to KSHV-induced cellular transformation by inhibiting ferroptosis. Mechanistically, KSHV-encoded viral interleukin-6 (vIL-6) hijacks SIRT3, a mitochondrial NAD+-dependent deacetylase, to interact with SERBP1 leading to the deacetylation of SERBP1. Deacetylated SERBP1 exhibits reduced binding to Lipt2 mRNA, which promotes Lipt2 mRNA degradation, resulting in ferroptosis inhibition. Our findings unveil a novel role of SERBP1 deacetylation in regulating ferroptosis and KSHV-induced cellular transformation and identify potential new therapeutic targets for KSHV infection and KSHV-induced cancers.铁死亡（ferroptosis）是宿主用以限制病原体感染的防御策略，其与多种肿瘤的发生发展及治疗应答密切相关。然而，铁死亡在卡波西肉瘤相关疱疹病毒（KSHV）诱导的恶性肿瘤中的作用仍有待阐明。越来越多的非组蛋白被鉴定为乙酰化修饰的靶标，但其相关功能尚未被揭示。本研究发现，多发性骨髓瘤（MM）细胞与KSHV转化的MM（KMM）细胞之间的乙酰化修饰谱存在显著差异。SERBP1去乙酰化在KMM细胞中上调，并通过抑制铁死亡促进KSHV诱导的细胞转化。从机制层面来看，KSHV编码的病毒白细胞介素-6（vIL-6）劫持线粒体烟酰胺腺嘌呤二核苷酸（NAD+）依赖的去乙酰化酶SIRT3，使其与SERBP1相互作用，进而介导SERBP1的去乙酰化修饰。去乙酰化后的SERBP1与Lipt2 mRNA的结合能力减弱，这一变化会促进Lipt2 mRNA的降解，最终实现铁死亡的抑制。本研究揭示了SERBP1去乙酰化在调控铁死亡及KSHV诱导的细胞转化中的全新功能，并为KSHV感染及KSHV相关恶性肿瘤提供了潜在的新型治疗靶点。