Roles and regulation of secretory and lysosomal acid sphingomyelinase.
Roles and regulation of secretory and lysosomal acid sphingomyelinase.
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DOI：
10.1016/j.cellsig.2009.01.026
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发表时间：
2009-06
影响因子：
4.8
通讯作者：
Hannun YA
中科院分区：
文献类型：
--
作者：
Jenkins RW;Canals D;Hannun YA
酸性鞘磷脂酶在鞘脂催化剂中占有重要地位，催化鞘磷脂水解为神经酰胺和磷酸胆碱。酸性鞘磷脂酶的酶功能障碍导致尼曼-匹克病，这是一种溶酶体贮积症，其特征在于在细胞水平上鞘磷脂在内-溶酶体隔室内积聚。在过去的十年中，对酸性鞘磷脂酶的作用的兴趣已经超越了其在溶酶体中鞘磷脂组成性周转中的“管家”功能，包括对调节神经酰胺生成的研究。神经酰胺作为一种具有多效性信号传导特性的生物活性鞘脂发挥作用，并参与多种具有重要生理和病理生理意义的细胞过程。虽然许多细胞酶都有能力产生神经酰胺，但越来越多的人认识到“所有的神经酰胺都是不平等的”。神经酰胺可能通过接触其他鞘脂酶（例如神经酰胺酶）、效应分子（例如神经酰胺活化的蛋白磷酸酶）以及邻近的脂质和蛋白质（例如胆固醇、离子通道）在不同的细胞/亚细胞区室中发挥不同的作用。酸性鞘磷脂酶的独特特征之一是它在三种不同的环境中参与鞘磷脂的水解-内溶酶体隔室、质膜的外小叶和脂蛋白。如何一个单一的基因产物有能力在这些不同的设置功能，以及随后对下游神经酰胺介导的生物学的影响是本次审查的主题。
Acid sphingomyelinase occupies a prominent position in sphingolipid catabolism, catalyzing the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Enzymatic dysfunction of acid sphingomyelinase results in Niemann-Pick disease, a lysosomal storage disorder characterized at the cellular level by accumulation of sphingomyelin within the endo-lysosomal compartment. Over the past decade interest in the role of acid sphingomyelinase has moved beyond its ‘housekeeping’ function in constitutive turnover of sphingomyelin in the lysosome to include study of regulated ceramide generation. Ceramide functions as a bioactive sphingolipid with pleiotropic signaling properties, and has been implicated in diverse cellular processes of physiologic and pathophysiologic importance. Though many cellular enzymes have the capacity to generate ceramide, there is growing appreciation that ‘all ceramides are not created equal.’ Ceramides likely exert distinct effects in different cellular/subcellular compartments by virtue of access to other sphingolipid enzymes (e.g. ceramidases), effector molecules (e.g. ceramide-activated protein phosphatases), and neighboring lipids and proteins (e.g. cholesterol, ion channels). One of the unique features of acid sphingomyelinase is that it has been implicated in the hydrolysis of sphingomyelin in three different settings – the endo-lysosomal compartment, the outer leaflet of the plasma membrane, and lipoproteins. How a single gene product has the capacity to function in these diverse settings, and the subsequent impact on downstream ceramide-mediated biology is the subject of this review.
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