Accumulating insights into the role of phospholipase D2 in human diseases

Phospholipase D2 (PLD2) is a lipid-signaling enzyme that produces the signaling molecule phosphatidic acid (PA) by catalyzing the hydrolysis of phosphatidylcholine (PC). The molecular characteristics of PLD2, the mechanisms of regulation of its activity, its functions in the signaling pathway involving PA and binding partners, and its role in cellular physiology have been extensively studied over the past decades. Although several potential roles of PLD2 have been proposed based on the results of molecular and cell-based studies, the pathophysiological functions of PLD2 in vivo have not yet been fully investigated at the organismal level. Here, we address accumulated evidences that provide insight into the role of PLD2 in human disease. We summarize recent studies using animal models that provide direct evidence of the function of PLD2 in several pathological conditions such as vascular disease, immunological disease, and neurological disease. In light of the use of recently developed PLD2-specific inhibitors showing potential in alleviating pathological conditions, improving our understanding of the role of PLD2 in human disease would be necessary to target the regulation of PLD2 activity as a therapeutic strategy.