MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
J Virol. 2019 Jan 17;93(3). doi: 10.1128/JVI.01747-18. Print 2019 Feb 1.
Chikungunya virus (CHIKV) is transmitted to people by mosquitoes, and CHIKV infection causes fever and joint pain. Fatty acid synthase (FASN) has been identified as a proviral factor for CHIKV. How FASN participates in CHIKV replication remains to be elucidated. In this study, we demonstrated that palmitic acid (PA) can restore the suppression of CHIKV replication by FASN inhibitors. The palmitoylation and plasma membrane localization of CHIKV nsP1 were reduced by FASN inhibitors. Triple mutation of Cys417, Cys418, and Cys419 in nsP1 blocked its palmitoylation and severely disrupted CHIKV replication. Furthermore, two zinc finger DHHC domain-containing palmitoyltransferases (ZDHHCs), ZDHHC2 and ZDHHC19, promoted nsP1 palmitoylation and CHIKV replication. Our results not only identified the key enzymes for the palmitoylation of nsP1 but also provided mechanistic insights into the roles of FASN in CHIKV replication. S-palmitoylation is an important form of lipid posttranslational modification, which affects the function of proteins by regulating their transport, stability, and localization. Previous studies have shown that FASN is critical for CHIKV replication; however, the mechanism for this function of FASN remains unknown. The key zinc finger DHHC domain-containing palmitoyltransferases involved in the palmitoylation of nsP1 are not clear. We demonstrated that FASN promoted CHIKV replication through nsP1 palmitoylation. ZDHHC2 and ZDHHC19 were identified as the major enzymes for nsP1 palmitoylation. Since nsP1 proteins are conserved in alphaviruses, our results highlight the mechanisms by which alphavirus nsP1 is palmitoylated.
基孔肯雅病毒（CHIKV）通过蚊子传播给人类，CHIKV 感染会引起发热和关节疼痛。脂肪酸合酶（FASN）已被确定为 CHIKV 的前病毒因子。FASN 如何参与 CHIKV 复制仍有待阐明。在这项研究中，我们证明棕榈酸（PA）可以恢复 FASN 抑制剂对 CHIKV 复制的抑制作用。FASN 抑制剂降低了 CHIKV nsP1 的棕榈酰化和质膜定位。nsP1 中的 Cys417、Cys418 和 Cys419 的三突变阻断了其棕榈酰化作用，并严重破坏了 CHIKV 的复制。此外，两种锌指 DHHC 结构域含棕榈酰转移酶（ZDHHCs），ZDHHC2 和 ZDHHC19，促进 nsP1 棕榈酰化和 CHIKV 复制。我们的研究结果不仅鉴定了 nsP1 棕榈酰化的关键酶，而且为 FASN 在 CHIKV 复制中的作用提供了机制上的见解。S-棕榈酰化是一种重要的脂质翻译后修饰形式，通过调节蛋白质的运输、稳定性和定位来影响蛋白质的功能。先前的研究表明，FASN 对 CHIKV 复制至关重要；然而，FASN 功能的机制尚不清楚。参与 nsP1 棕榈酰化的关键锌指 DHHC 结构域含棕榈酰转移酶尚不清楚。我们证明 FASN 通过 nsP1 棕榈酰化促进 CHIKV 复制。ZDHHC2 和 ZDHHC19 被鉴定为 nsP1 棕榈酰化的主要酶。由于 nsP1 蛋白在甲病毒中保守，我们的结果突出了甲病毒 nsP1 棕榈酰化的机制。
