Abstract
Individual members of the mammalian phospholipase D (PLD) superfamily undertake roles that extend from generating the second messenger signaling lipid, phosphatidic acid, through hydrolysis of the membrane phospholipid, phosphatidylcholine, to functioning as an endonuclease to generate small RNAs and facilitating membrane vesicle trafficking through seemingly nonenzymatic mechanisms. With recent advances in genome-wide association studies, RNA interference screens, next-generation sequencing approaches, and phenotypic analyses of knockout mice, roles for PLD family members are being uncovered in autoimmune, infectious neurodegenerative, and cardiovascular disease, as well as in cancer. Some of these disease settings pose opportunities for small molecule inhibitory therapeutics, which are currently in development.
Highlights
Individual members of the mammalian phospholipase D (PLD) superfamily undertake roles that extend from generating the second messenger signaling lipid, phosphatidic acid, through hydrolysis of the membrane phospholipid, phosphatidylcholine, to functioning as an endonuclease to generate small RNAs and facilitating membrane vesicle trafficking through seemingly nonenzymatic mechanisms
This key finding suggests that PLD3 undergoes cytoplasmic ubiquitination and could be recognized and sorted by Hrs to co-traffic with amyloid peptide (A)PP from endosomes to luminal vesicles of multivesicular body (MVB). Supporting this hypothesis, a PLD3 allele with significant association with late-onset Alzheimer’s disease (AD), in which methionine 6 is substituted for by arginine (M6R), occurs in an amino acid residue close to K11 and could potentially affect ubiquitination, providing a basis for its disease linkage. These data, taken together, suggest that if ubiquitinated, Hrstrafficked PLD3 plays a role in moving APP from early endosomes to luminal vesicles of MVBs for eventual lysosomal degradation; a decrease in or a lack of ubiquitination, as well as nonfunctional PLD3, could cause APP retention in early endosomes and increased A production to promote AD pathology
PLD4 deficiency in humans has been linked through genome-wide association studies to syndromes such as rheumatoid arthritis [100] and the autoimmune disease systemic sclerosis [101]. These findings suggest that PLD4 deficiency results in hyper-activation of the immune system, causing a variety of autoimmune-like syndromes
Summary
The mammalian phospholipase D (PLD) superfamily is best known for the catalytic action of its classical family members which hydrolyze phosphatidylcholine, the most abundant membrane phospholipid, to generate choline and the second messenger signaling lipid, phosphatidic acid (PA) [1]. The ability of PLD2 to use glycerol as a nucleophile to generate phosphatidylglycerol has been proposed to play roles in wound healing [11, 12]. Both PLD1 and PLD2 have been proposed to undertake roles in many cell biological and physiological settings, as will be described subsequently. PLD6 (MitoPLD) has been reported to hydrolyze cardiolipin on the outer surface of the mitochondria to generate PA [13], as well as to function as an endonuclease Definitive cellular and physiological roles for PLD5 have not yet been identified
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