Interaction/Oligomerization of Nucleoside Diphosphate Kinase Isoforms in Pathological Processes

核苷二磷酸激酶（NDPK）是催化末端磷酸基团转移的酶，主要是从三磷酸腺苷（ATP）转移到核苷二磷酸（NDP），从而补充各种细胞过程所需的核苷三磷酸（NTP）池。I类亚家族由NDPK A、B、C和D同工异构体组成，具有酶活性，已知可形成同质和异质六聚体。虽然NDPK D在线粒体内膜中具有特定的作用，但NDPK C在其他三种同工异构体中的作用却不太明确，其中NDPK C的表达量低于NDPK a和NDPK B。除了维持细胞NTP池的作用外，NDPK B在细胞生长、分化和信号传导中具有特定的细胞功能。我们之前已经确定NDPK B在细胞葡萄糖代谢中的重要作用，特别是在己糖胺生物合成途径和蛋白o - glcn酰化中。此外，我们报道了NDPK B和NDPK C复合物的形成控制了其向质膜的转运及其与异三聚体G蛋白的相互作用，这有助于人类心力衰竭中心肌细胞cAMP形成的失调。由于我们的初步数据表明NDPK B通过调节心脏蛋白o - glcn酰化在心肌病中的作用，我们假设NDPK B和NDPK C的合作或相互作用可能在糖尿病心肌病的发展中很重要。因此，本研究旨在(1)利用链脲霉素诱导的野生型和NDPK B缺陷小鼠糖尿病模型，阐明NDPK B和NDPK C在代谢性心肌病中的作用和相互作用；(2)研究NDPK B和NDPK C在体外不同心肌细胞类型细胞糖代谢中的相互作用/寡聚。

Nucleoside diphosphate kinases (NDPK) are enzymes that catalyze the transfer of terminal phosphate groups, mainly from adenosine triphosphate (ATP), to nucleoside diphosphates (NDP) and thus replenish nucleoside triphosphate (NTP) pools required for a wide variety of cellular processes. The class I subfamily, consisting of the isoforms NDPK A, B, C, and D, possess enzymatic activity and are known to form homo-and hetero-hexamers. Whereas NDPK D has a specific role in the mitochondrial inner membrane, the role of the other three isoforms, of which NDPK C is less abundantly expressed than NDPK A and NDPK B, is less well defined. In addition to its role in contributing to the upkeep of the cellular NTP pool, NDPK B has specific cellular functions in cell growth, differentiation, and signaling. We have previously established the essential role of NDPK B in cellular glucose metabolism, especially in the hexosamine biosynthesis pathway and protein O-GlcNAcylation. Additionally we reported that the formation of an NDPK B and NDPK C complex governs its translocation to the plasma membrane and its interaction with heterotrimeric G proteins, which contributes to the dysregulation of cardiomyocyte cAMP formation in human heart failure. As our preliminary data point to a role of NDPK B in cardiomyopathy by regulating cardiac protein O-GlcNAcylation, we hypothesize that a cooperation or interaction of NDPK B and NDPK C might be important in the development of diabetic cardiomyopathy. This proposal therefore aims (1) to elucidate the role and interaction of NDPK B and NDPK C in metabolic cardiomyopathy by using the streptozotocin-induced diabetes model in wild type and NDPK B deficient mice, (2) to investigate the interaction/oligomerization of NDPK B and NDPK C in cellular glucose metabolisms in different cardiac cell types in vitro.