Patatin-domain-containing (phospho)lipases under control: Mammalian co-regulators and pathogenic activation mechanisms.

Patatin-like phospholipase (PNPLA) domain-containing proteins are essential enzymes involved in lipid metabolism, membrane remodeling, and signaling pathways across various organisms. This review focuses on the structural and functional characteristics of four selected PNPLA proteins from different organisms with experimental 3D structures or biochemical data on protein-protein interactions that facilitate their co-activation mechanism, namely VipD, ExoU, PNPLA9, and PNPLA2 (also known as ATGL). VipD and ExoU, phospholipases from Legionella pneumophila and Pseudomonas aeruginosa, respectively, are multidomain proteins and utilize distinct mechanisms for host cell interaction and pathogenesis. VipD binds to Rab proteins, underscoring the critical role of Rab5 in upregulating its enzymatic activity and contributing to the pathogenicity. ExoU requires ubiquitin for activation and exhibits an inhibited structure when complexed with its chaperone SpcU. PNPLA9, a calcium-independent phospholipase A2, is predominantly expressed in the human brain, with mutations linked to neurodegenerative disorders and inflammation. The crystal structure of the Chinese hamster ortholog of PNPLA9 reveals a dimerization mechanism required for its catalytic activity, along with specific regions identified for membrane interaction and substrate binding. PNPLA2 is known for its triacylglycerol hydrolytic activity and is regulated by protein-protein interactions, particularly with the co-activator ABHD5, which is crucial for its activation. This review highlights the diversity and conserved architectural segments of PNPLA proteins, reflecting their varied biological roles and regulatory mechanisms. Understanding the diverse protein-protein interactions that activate these enzymes is crucial for elucidating their roles in physiological and pathological contexts.