Targeting ACLY efficiently inhibits SARS-CoV-2 replication

Yuen, Terrence Tsz‐Tai; Chan, Jasper Fuk‐Woo; Yan, Bingpeng; Shum, Cynthia Cheuk-Ying; Liu, Yuanchen; Shuai, Huiping; Hou, Yuxin; Huang, Xiner; Hu, Bingjie; Chai, Yue; Yoon, Chaemin; Zhu, Tianrenzheng; Liu, Huan; Shi, Jialu; Zhang, Jinjin; Cai, Jian‐Piao; Zhang, Anna Jinxia; Zhou, Jie; Yin, Feifei; Yuan, Shuofeng; Zhang, Baozhong; Chu, Hin

doi:10.7150/ijbs.72709

Cited by 9 publications

(4 citation statements)

References 69 publications

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“…Our current understanding of the role of ACLY in virus replication is limited. While chemical and genetic inhibition of ACLY suppressed the replication of SARS-CoV-2 (75), indicating it could be an important host factor governing the replication of the virus, it is yet unclear if the virus increases the phosphorylation or activity of ACLY. Another study in transformed HCC cells and transgenic mice expressing the Hepatitis B virus pre-S2 mutant in the liver showed increased ACLY phosphorylation through mTOR signaling to induce the levels of neutral lipids such as triglycerides and cholesterol (76), without showing direct effect of HBV infection on ACLY levels.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of ATP Citrate Lyase Phosphorylation and Neutral Lipid Synthesis through Viral Growth Factor Signaling during Vaccinia Virus Infection

Pant,

Brahim Belhaouari,

Dsouza

et al. 2023

Preprint

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Like all other viruses, poxviruses rely on host cells to provide metabolites and energy. Vaccinia virus (VACV), the prototype poxvirus, induces profound metabolic alterations in host cells. We previously showed that VACV infection increases the tricarboxylic acid (TCA) cycle intermediates, including citrate, that can be transported to the cytosol to be converted to acetyl-CoA for de novo fatty acid biosynthesis. ATP citrate lyase (ACLY) is a pivotal enzyme converting citrate to acetyl-CoA. Here, we report that VACV infection stimulates the S455 phosphorylation of ACLY, a post-translational modification that stimulates ACLY activity. We demonstrate that the chemical and genetic inhibition of ACLY severely suppresses VACV replication. Remarkably, we found that virus growth factor (VGF)- induced signaling is essential for the VACV-mediated upregulation of ACLY phosphorylation. Furthermore, the upregulation of ACLY phosphorylation during VACV infection is dependent on the activation of the cellular Akt kinase that phosphorylates ACLY. Finally, we report that VGF-induced ACLY phosphorylation via the EGFR-Akt pathway is important for VACV stimulations of neutral lipid droplet synthesis. These findings identified a previously unknown way of rewiring cell metabolism by a virus and a novel function for VGF in the governance of virus-host interactions through the induction of a key enzyme at the crossroads of the TCA cycle and fatty acid de novo biosynthesis. Our study also provides a mechanism for the role played by VGF and its downstream signaling cascades in the modulation of lipid metabolism in VACV-infected cells.

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Section: Discussionmentioning

confidence: 99%

Upregulation of ATP Citrate Lyase Phosphorylation and Neutral Lipid Synthesis through Viral Growth Factor Signaling during Vaccinia Virus Infection

Pant,

Brahim Belhaouari,

Dsouza

et al. 2023

Preprint

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“…The significance of advanced COVID-19 diagnostic testing in pandemic control measures. Int J Biol Sci 2022; 18 (12):4610-4617. doi:10.7150/ijbs.72837. apply these diagnostic tests optimally in the community to cope with the ever-changing pandemic conditions.…”

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confidence: 99%

“…They concluded that the primary roles of the N protein are to assemble with genomic RNA into the viral RNAprotein (vRNP) complex and to localize to the replication transcription complexes (RTCs) to enhance viral replication and transcription. Yuen et al 12 reported their work in the identification of ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. Thus, ACLY should be further explored as a novel intervention target for COVID-19.…”

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confidence: 99%