PLD6 Protein, Human

PLD6 is a protein exhibiting phospholipase and nuclease activities, with its functional role varying under different physiological conditions. Interaction with Mitoguardin (MIGA1 or MIGA2) modulates its dimer conformation, favoring phospholipase over nuclease activity. It plays a pivotal role in mitochondrial fusion and fission through its phospholipase activity, utilizing the mitochondrial lipid cardiolipin as a substrate to generate phosphatidate (PA or 1,2-diacyl-sn-glycero-3-phosphate), a second messenger signaling lipid. PA production facilitates Mitofusin-mediated fusion, while its cleavage by Lipin phosphatases yields diacylgycerol (DAG), promoting mitochondrial fission. Lipin and DAG collectively regulate mitochondrial dynamics and membrane fusion/fission, essential for adapting mitochondrial metabolism to cellular physiological changes. Mitochondrial fusion enables cells to meet increased nucleotide demands during DNA synthesis. Mitochondrial function and dynamics are closely linked to biological processes such as cell growth, proliferation, and differentiation. As a mediator of MYC activity, PLD6 promotes mitochondrial fusion and activates AMPK, which inhibits YAP/TAZ, thereby inducing cell growth and proliferation. Its nuclease activity is critical for PIWI-interacting RNA (piRNA) biogenesis during spermatogenesis, playing a key role in testicular germ cell fertility. MOV10L1 selectively binds piRNA precursors and directs them to the endonuclease, catalyzing the first cleavage step in piRNA processing to generate intermediate fragments subsequently loaded onto Piwi proteins. PLD6 cleaves DNA or RNA substrates with similar affinity, producing 5' phosphate ends, thus participating in primary piRNA transcript processing. piRNAs provide essential protection against mobile genetic elements, with piRNA-mediated transposon silencing being crucial for genome stability, especially in germline cells during widespread genomic demethylation (By similarity). PA may act as a signaling molecule in the recognition/transport of primary piRNA precursor RNAs. PLD6 interacts with tesmin in testes, suggesting a role in spermatogenesis via its interacting partner (By similarity).