ABHD16A Negatively Regulates the Palmitoylation and Antiviral Function of IFITM Proteins

Interferon-inducible transmembrane (IFITM) proteins are small homologous proteins that are encoded by the interferon-stimulated genes (ISGs), which can be strongly induced by interferon (IFN) and provide resistance to invasion by a variety of viral pathogens. However, the exact molecular mechanisms underlying this function have remained elusive. The antiviral activity of IFITMs from different species depends on S-palmitoylation at conserved cysteine residues. However, specific enzymes involved in the dynamic palmitoylation cycle of IFITMs, especially depalmitoylase, have not yet been reported. Here, we demonstrate that α/-hydrolase domain-containing 16A (ABHD16A) is a depalmitoylase and a negative regulator of IFITM protein that can catalyze the depalmitoyl reaction of S-palmitoylated IFITM proteins, thereby decreasing their antiviral activities on RNA viruses. Using the acyl-PEGyl exchange gel shift (APEGS) assay, we identified ABHD16A proteins from humans, pigs, and mice that can directly participate in the palmitoylation/depalmitoylation cycles of IFITMs in the constructed abhd16a(−/−) cells and ABHD16A-overexpressing cells. Furthermore, we showed that ABHD16A functions as a regulator of subcellular localization of IFITM proteins and is related to the immune system. It is tempting to suggest that pharmacological intervention in IFITMs and ABHD16A can be achieved either through controlling their expression or regulating their activity, thereby providing a broad-spectrum therapeutic strategy for animal viral diseases.