Proteome-Scale Analysis of Protein <i>S</i>‑Acylation Comes of Age

Protein S-acylation (commonly known as palmitoylation) is a widespread reversible lipid modification, which plays critical roles in regulating protein localization, activity, stability, and complex formation. The deregulation of protein S-acylation contributes to many diseases such as cancer and neurodegenerative disorders. The past decade has witnessed substantial progress in proteomic analysis of protein S-acylation, which significantly advanced our understanding of S-acylation biology. In this review, we summarized the techniques for the enrichment of S-acylated proteins or peptides, critically reviewed proteomic studies of protein S-acylation at eight different levels, and proposed major challenges for the S-acylproteomics field. In summary, proteome-scale analysis of protein S-acylation comes of age and will play increasingly important roles in discovering new disease mechanisms, biomarkers, and therapeutic targets.