PDF(Pubmed)
Abstract：
Phosphatidylinositol (PI) is the precursor lipid for the minor phosphoinositides (PPIns), which are critical for multiple functions in all eukaryotic cells. It is poorly understood how phosphatidylinositol, which is synthesized in the ER, reaches those membranes where PPIns are formed. Here, we used VT01454, a recently identified inhibitor of class I PI transfer proteins (PITPs), to unravel their roles in lipid metabolism, and solved the structure of inhibitor-bound PITPNA to gain insight into the mode of inhibition. We found that class I PITPs not only distribute PI for PPIns production in various organelles such as the plasma membrane (PM) and late endosomes/lysosomes, but that their inhibition also significantly reduced the levels of phosphatidylserine, di- and triacylglycerols, and other lipids, and caused prominent increases in phosphatidic acid. While VT01454 did not inhibit Golgi PI4P formation nor reduce resting PM PI(4,5)P2 levels, the recovery of the PM pool of PI(4,5)P2 after receptor-mediated hydrolysis required both class I and class II PITPs. Overall, these studies show that class I PITPs differentially regulate phosphoinositide pools and affect the overall cellular lipid landscape.
摘要：
磷脂酰肌醇（PI）是次要磷酸肌醇（PPIns）的前体脂质，这对所有真核细胞的多种功能至关重要。磷脂酰肌醇是如何理解的，在ER中合成，到达形成PPIns的那些膜。这里,我们使用VT01454，一种最近鉴定的I类PI转移蛋白（PITP）抑制剂，解开它们在脂质代谢中的作用，并解析了与抑制剂结合的PITPNA的结构，以深入了解抑制模式。我们发现，I类PITP不仅在各种细胞器（例如质膜（PM）和晚期内体/溶酶体）中分配用于PPIns产生的PI，但是它们的抑制作用也显著降低了磷脂酰丝氨酸的水平，二-和三酰基甘油，和其他脂质，并导致磷脂酸的显著增加。虽然VT01454既不抑制高尔基PI4P形成也不降低静息PMPI(4,5)P2水平,受体介导的水解后，PI（4,5）P2的PM库的恢复需要I类和II类PITP。总的来说,这些研究表明，I类PITP差异调节磷酸肌醇集合，并影响整体细胞脂质景观。
