Hangzhou, June 2025 – The research team from Zhejiang University has published new findings in the latest issue of Cell Investigation journal, unveiling a novel mechanism of SMURF2 palmitoylation that contributes to the regulation of lipid synthesis. The study demonstrates that ZDHHC9 regulates lipid synthesis by palmitoylating SMURF2, which enhances lipid synthesis and lipid droplet formation. This discovery presents a potential new target for the treatment of metabolic diseases such as obesity.
Lipid synthesis in adipocytes is essential for maintaining energy balance and cell function. In recent years, a novel protein modification in adipocytes, palmitoylation, has attracted significant attention. Palmitoylation, a post-translational modification mediated by DHHC-type palmitoyltransferases, adds palmitic acid to cysteine residues on proteins, thus regulating membrane attachment, stability, and function. However, the role of palmitoylation in lipid synthesis, especially in the function of the key protein SMURF2, has remained unclear. The study reveals the mechanism by which SMURF2 regulates lipid synthesis through palmitoylation.
The research identifies ZDHHC9 as the primary palmitoyltransferase responsible for palmitoylating SMURF2. ZDHHC9 interacts with SMURF2 to catalyze its palmitoylation, enhancing its stability and enzymatic activity. Following palmitoylation, SMURF2 promotes glucose-derived palmitic acid synthesis in mouse adipocytes, which drives lipid droplet formation. The study shows that SMURF2 undergoes palmitoylation at three cysteine sites (Cys20, Cys118, and Cys743), and this modification is crucial for SMURF2’s stability and membrane binding. In the experiments, SMURF2’s palmitoylation level significantly increased in the presence of ZDHHC9, enhancing its stability in adipocytes and further promoting lipid synthesis.
ZDHHC9 not only acts as the main palmitoyltransferase for SMURF2, but also regulates its stability, promoting its function in adipocytes. Overexpression of ZDHHC9 enhances SMURF2 palmitoylation, thus promoting glucose oxidation and fatty acid synthesis. This discovery provides a new molecular mechanism for regulating lipid synthesis and offers a new direction for anti-obesity therapy. In a mouse adipocyte model overexpressing SMURF2 and ZDHHC9, the researchers found that changes in glucose metabolism directly promoted lipid synthesis. Specifically, overexpression of SMURF2 and ZDHHC9 increased glucose oxidation and the de novo synthesis of palmitic acid, ultimately promoting lipid droplet formation.
This study is the first to reveal the key role of SMURF2 palmitoylation mediated by ZDHHC9 in lipid synthesis. The findings provide new insights into the function of SMURF2 and offer a theoretical basis for future applications in metabolic diseases such as obesity and diabetes. By regulating ZDHHC9 and its palmitoylation process, new potential targets for anti-obesity therapies may emerge. With further exploration of protein post-translational modification mechanisms, palmitoylation, as a dynamic and reversible modification, will open new research avenues for lipid metabolism and related diseases. In the future, researchers may focus on investigating the role of ZDHHC9 in other cell types, especially in tumor cells and metabolic diseases.
Full Article Link: https://www.sciencedirect.com/science/article/pii/S3050538025000092