S- acylation of PNPLA2/ATGL: a necessity for triacylglycerol lipolysis and lipophagy in hepatocytes

The intricate balance between lipolysis and lipophagy in cellular lipid homeostasis has fascinated researchers for years. A growing body of evidence highlights the critical roles of PNPLA2/ATGL (patatin like phospholipase domain containing 2) in both lipolysis and lipophagy. Here, we discuss our recent study, which revealed that PNPLA2 must be S-acylated on Cys15 for its robust catalytic activity. Additionally, we discuss the results highlighting that genetic inactivation of the ZDHHC11 acyltransferase or expression of S-acylation deficient PNPLA2 mutants impairs not only lipolysis but also lipophagy. This finding suggests that the mere presence of PNPLA2 with its LC3-interacting region (LIR) motifs is insufficient to drive lipophagy without triacylglycerol breakdown. Our study provides insights into yet another mode of regulation of PNPLA2 activity with implications for understanding lipid droplet catabolism, lipophagy, and cellular energy homeostasis.