Fatty Acid Synthase Promotes the Palmitoylation of Chikungunya Virus nsP1

Abstract

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 domaincontaining 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. IMPORTANCE 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.

Intraviral interactome of Chikungunya virus reveals the homo-oligomerization and palmitoylation of structural protein TF

“…Protein palmitoylation plays a key role in regulating protein localization and function. For instance, palmitoylation is critical for the plasma membrane localization of nsP1 from CHIKV [7]. Here, we identified that CHIKV TF was palmitoylated to promote its interaction with nonstructural proteins.…”

“…Recently, we demonstrated that CHIKV nsP1 is palmitoylated. Mutations that prevented nsP1 palmitoylation reduced the CHIKV infection [7]. TF from Sindbis virus (SINV) was reported to be palmitoylated [8].…”

A highly efficient in vivo plasmid editing tool based on CRISPR-Cas12a and phage λ Red recombineering

“…To further test the robustness of our system, we attempted to manipulate different types of high-copy plasmids used for research on bacteria and viruses such as chikungunya virus (Mainou et al, 2013;Zhang et al, 2019). These plasmids are large and do not contain appropriate restriction enzyme sites, making them difficult to manipulate using regular methods, but they can be easily manipulated by our developed system to generate point mutations, deletions, and insertions with efficiencies from 33% to 100% (Table S2).…”

Selective Docking of Pyranooxazoles Against nsP2 of CHIKV Eluted Through Isothermally and Non‐Isothermally MD simulations

“…It shows various activities like NTPase, RNA triphosphatase etc . It is important to understand the importance or function of the non‐structural polyproteins in pathogenicity . nsP2 of CHIKV is a significant pathogenic delegate of alphavirus and participate in different enzymatic reaction .…”

“…It is important to understand the importance or function of the non‐structural polyproteins in pathogenicity . nsP2 of CHIKV is a significant pathogenic delegate of alphavirus and participate in different enzymatic reaction . Researchers showed their interest in the finding of the small molecules targeting the nsP2.…”