Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities

Protein lipidation is an important co- or posttranslational modification in which lipid moieties are covalently attached to proteins. Lipidation markedly increases the hydrophobicity of proteins, resulting in changes to their conformation, stability, membrane association, localization, trafficking, and binding affinity to their co-factors. Various lipids and lipid metabolites serve as protein lipidation moieties. The intracellular concentrations of these lipids and their derivatives are tightly regulated by cellular metabolism. Therefore, protein lipidation links the output of cellular metabolism to the regulation of protein function. Importantly, deregulation of protein lipidation has been linked to various diseases, including neurological disorders, metabolic diseases, and cancers. In this review, we highlight recent progress in our understanding of protein lipidation, in particular, S-palmitoylation and lysine fatty acylation, and we describe the importance of these modifications for protein regulation, cell signaling, and diseases. We further highlight opportunities and new strategies for targeting protein lipidation for therapeutic applications.