Productive Mayaro Virus Infection Requires Host Fatty Acid Synthase for nsP1 S-palmitoylation

Area of Science:

• Virology
• Molecular Biology
• Biochemistry

Background:

• Twenty-seven pathogenic viruses utilize host fatty acid biosynthesis, driven by fatty acid synthase (FASN), for replication.
• FASN produces palmitate, essential for viral functions like assembly, energy generation, and protein modification.
• The role of FASN in Mayaro virus (MAYV) infection, an alphavirus causing arthritogenic disease, was previously unknown.

Purpose of the Study:

• To investigate whether MAYV replication is dependent on FASN-mediated palmitate synthesis.
• To identify the specific downstream pathways of FASN that contribute to MAYV infection.
• To explore the potential of targeting FASN as an antiviral strategy against MAYV.

Main Methods:

• Genetic and pharmacological approaches were used in human cell lines and primary cells.
• Inhibition of FASN and downstream pathways, including protein palmitoylation using 2-bromopalmitate (2-BP).
• Metabolic labeling with alkyne palmitate analog (Alk-4) to detect protein palmitoylation of MAYV nonstructural protein 1 (nsP1).

Main Results:

• MAYV virion production requires FASN-dependent palmitate synthesis.
• Inhibition of protein palmitoylation with 2-BP reduced MAYV infection by 94%.
• MAYV nsP1 undergoes FASN-dependent S-palmitoylation at conserved cysteine residues, confirmed by Alk-4 labeling experiments.

Conclusions:

• MAYV infection is critically dependent on FASN-catalyzed palmitate synthesis.
• Protein palmitoylation is a conserved, essential mechanism for alphavirus replication, including MAYV.
• FASN represents a promising antiviral target for MAYV and potentially other alphaviruses.