The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (11), p.1-12
• Main Authors: Foo, Alexander C. Y., Thompson, Peter M., Chen, Shih-Heng, Jadi, Ramesh, Lupo, Brianna, DeRose, Eugene F., Arora, Simrat, Placentra, Victoria C., Premkumar, Lakshmanane, Perera, Lalith, Pedersen, Lars C., Martin, Negin, Mueller, Geoffrey A.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral activity; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Aquatic insects; Biological Sciences; Blood meals; Cell Line; Cell Membrane - metabolism; Coronaviruses; Culicidae; Cytolytic activity; Dengue fever; Displays; Erythrocytes - drug effects; Fatty acids; Fatty Acids, Unsaturated - metabolism; Hemolytic Agents - chemistry; Hemolytic Agents - metabolism; Hemolytic Agents - pharmacology; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Insect Proteins - chemistry; Insect Proteins - metabolism; Insect Proteins - pharmacology; Lecithin; Ligands; Lipid bilayers; Lipids; Lipids - chemistry; Meals; Mosquitoes; Phosphatidylcholine; Protein Binding; Protein Structure, Tertiary; Proteins; Vector-borne diseases; Viral Envelope - metabolism; Viruses; Viruses - drug effects; Viruses - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2019251118

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity.We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broadspectrum therapeutic against cellular and viral targets.