Host Protein Palmitoylation: A Two-Edged Sword in the Pathogenesis of COVID-19

Protein palmitoylation is a two-edged sword in regulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. On the one hand, SARS-CoV-2 hijacks the host’s palmitoyl transferases (ZDHHC5/9/20) to modify its spike protein (S protein), enhancing its stability, membrane anchoring, and fusion, consequently facilitating SARS-CoV-2 entry, replication, and release. On the other hand, the host utilises this modification to activate antiviral defences: palmitoylation of the mitochondrial antiviral signalling protein (MAVS) leads to its accumulation in the mitochondria and initiates interferon signalling; palmitoylation of the stimulator of interferon genes (STING) is essential for its activation and transport; and palmitoylation of interferon-induced transmembrane protein 3 (IFITM3) increases its ability to inhibit SARS-CoV-2 membrane fusion. This defensive–offensive interplay within the same regulatory system offers fresh opportunities for targeted therapy, including the development of specific ZDHHC inhibitors, palmitoylated angiotensin-converting enzyme 2 (ACE2)-based decoy vesicles, and metabolic intervention approaches. In the future, it will be necessary to conduct in-depth analyses of the functions of key modification sites and develop precise regulatory strategies to address the ongoing threat posed by coronaviruses.