Kamat Siddhesh S, Camara Kaddy, Parsons William H, Chen Dong-Hui, Dix Melissa M, Bird Thomas D, Howell Amy R, Cravatt Benjamin F
1] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California. [2] The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California.
Department of Chemistry, University of Connecticut, Storrs, Connecticut.
Nat Chem Biol. 2015 Feb;11(2):164-71. doi: 10.1038/nchembio.1721. Epub 2015 Jan 12.
Lysophosphatidylserines (lyso-PSs) are a class of signaling lipids that regulate immunological and neurological processes. The metabolism of lyso-PSs remains poorly understood in vivo. Recently, we determined that ABHD12 is a major brain lyso-PS lipase, implicating lyso-PSs in the neurological disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC), which is caused by null mutations in the ABHD12 gene. Here, we couple activity-based profiling with pharmacological and genetic methods to annotate the poorly characterized enzyme ABHD16A as a phosphatidylserine (PS) lipase that generates lyso-PS in mammalian systems. We describe a small-molecule inhibitor of ABHD16A that depletes lyso-PSs from cells, including lymphoblasts derived from subjects with PHARC. In mouse macrophages, disruption of ABHD12 and ABHD16A respectively increases and decreases both lyso-PSs and lipopolysaccharide-induced cytokine production. Finally, Abhd16a(-/-) mice have decreased brain lyso-PSs, which runs counter to the elevation in lyso-PS in Abhd12(-/-) mice. Our findings illuminate an ABHD16A-ABHD12 axis that dynamically regulates lyso-PS metabolism in vivo, designating these enzymes as potential targets for treating neuroimmunological disorders.
溶血磷脂酰丝氨酸（lyso-PSs）是一类调节免疫和神经过程的信号脂质。在体内，lyso-PSs的代谢仍知之甚少。最近，我们确定ABHD12是一种主要的脑lyso-PS脂肪酶，这表明lyso-PSs与由ABHD12基因无效突变引起的神经疾病多神经病、听力丧失、共济失调、色素性视网膜炎和白内障（PHARC）有关。在这里，我们将基于活性的分析方法与药理学和遗传学方法相结合，以阐明特征不明的酶ABHD16A是一种在哺乳动物系统中产生lyso-PS的磷脂酰丝氨酸（PS）脂肪酶。我们描述了一种ABHD16A的小分子抑制剂，它能从细胞中耗尽lyso-PSs，包括来自PHARC患者的淋巴母细胞。在小鼠巨噬细胞中，ABHD12和ABHD16A的破坏分别增加和减少lyso-PSs以及脂多糖诱导的细胞因子产生。最后，Abhd16a(-/-)小鼠的脑lyso-PSs减少，这与Abhd12(-/-)小鼠中lyso-PS的升高相反。我们的研究结果揭示了一个ABHD16A-ABHD12轴，该轴在体内动态调节lyso-PS代谢，将这些酶指定为治疗神经免疫疾病的潜在靶点。
