Table_2_The Structure and Function of Acylglycerophosphate Acyltransferase 4/ Lysophosphatidic Acid Acyltransferase Delta (AGPAT4/LPAATδ).xlsx

Lipid-modifying enzymes serve crucial roles in cellular processes such as signal transduction (producing lipid-derived second messengers), intracellular membrane transport (facilitating membrane remodeling needed for membrane fusion/fission), and protein clustering (organizing lipid domains as anchoring platforms). The lipid products crucial in these processes can derive from different metabolic pathways, thus it is essential to know the localization, substrate specificity, deriving products (and their function) of all lipid-modifying enzymes. Here we discuss an emerging family of these enzymes, the lysophosphatidic acid acyltransferases (LPAATs), also known as acylglycerophosphate acyltransferases (AGPATs), that produce phosphatidic acid (PA) having as substrates lysophosphatidic acid (LPA) and acyl-CoA. Eleven LPAAT/AGPAT enzymes have been identified in mice and humans based on sequence homologies, and their localization, specific substrates and functions explored. We focus on one member of the family, LPAATδ, a protein expressed mainly in brain and in muscle (though to a lesser extent in other tissues); while at the cellular level it is localized at the trans-Golgi network membranes and at the mitochondrial outer membranes. LPAATδ is a physiologically essential enzyme since mice knocked-out for Lpaatδ show severe dysfunctions including cognitive impairment, impaired force contractility and altered white adipose tissue. The LPAATδ physiological roles are related to the formation of its product PA. PA is a multifunctional lipid involved in cell signaling as well as in membrane remodeling. In particular, the LPAATδ-catalyzed conversion of LPA (inverted-cone-shaped lipid) to PA (cone-shaped lipid) is considered a mechanism of deformation of the bilayer that favors membrane fission. Indeed, LPAATδ is an essential component of the fission-inducing machinery driven by the protein BARS. In this process, a protein-tripartite complex (BARS/14-3-3γ/phosphoinositide kinase PI4KIIIβ) is recruited at the trans-Golgi network, at the sites where membrane fission is to occur; there, LPAATδ directly interacts with BARS and is activated by BARS. The resulting formation of PA is essential for membrane fission occurring at those spots. Also in mitochondria PA formation has been related to fusion/fission events. Since PA is formed by various enzymatic pathways in different cell compartments, the BARS-LPAATδ interaction indicates the relevance of lipid-modifying enzymes acting exactly where their products are needed (i.e., PA at the Golgi membranes).

脂质修饰酶在细胞信号转导（产生脂质衍生的第二信使）、细胞内膜运输（促进膜融合/裂解所需的膜重塑）以及蛋白质聚簇（组织脂质区域作为锚定平台）等细胞过程中发挥着至关重要的作用。在这些过程中至关重要的脂质产物可以来源于不同的代谢途径，因此了解所有脂质修饰酶的定位、底物特异性、衍生产物（及其功能）至关重要。在本研究中，我们讨论了这些酶中一个新兴家族——溶血磷脂酸酰基转移酶（LPAATs），也称为酰基甘油磷酸酰基转移酶（AGPATs），它们以溶血磷脂酸（LPA）和酰基辅酶A（acyl-CoA）为底物，产生磷脂酸（PA）。基于序列同源性，已在小鼠和人类中鉴定出11种LPAAT/AGPAT酶，并对其定位、底物特异性和功能进行了探索。我们聚焦于该家族的一员，LPAATδ，这是一种主要在脑部和肌肉中表达（尽管在其他组织中表达程度较低）的蛋白质；在细胞水平上，它定位于高尔基体网络膜和线粒体外膜。LPAATδ是一种生理上必需的酶，因为敲除Lpaatδ基因的小鼠表现出严重的功能障碍，包括认知障碍、力量收缩性受损和白色脂肪组织改变。LPAATδ的生理作用与其产物PA的形成密切相关。PA是一种多功能脂质，参与细胞信号传导以及膜重塑。特别是，LPAATδ催化的LPA（倒锥形脂质）转化为PA（锥形脂质）被认为是双层膜变形的机制，有利于膜裂解。实际上，LPAATδ是蛋白质BARS驱动的裂解诱导机器的必要组成部分。在这个过程中，一个蛋白质三联体复合物（BARS/14-3-3γ/磷脂酰肌醇激酶PI4KIIIβ）在膜裂解将发生的转高尔基网络中被招募；在那里，LPAATδ直接与BARS相互作用并由BARS激活。由此产生的PA形成对于在那些点发生膜裂解至关重要。此外，在线粒体中，PA的形成与融合/裂解事件有关。由于PA是由不同细胞区室中不同的酶促途径形成的，BARS-LPAATδ的相互作用表明脂质修饰酶的作用与其产物所需的确切位置相关（即，PA在高尔基膜上）。