Compartmentalization of Mammalian Pantothenate Kinases

The pantothenate kinases (PanK) catalyze the first and the rate-limiting step in coenzyme A (CoA) biosynthesis and regulate the amount of CoA in tissues by differential isoform expression and allosteric interaction with metabolic ligands. The four human and mouse PanK proteins share a homologous carboxy-terminal catalytic domain, but differ in their amino-termini. These unique termini direct the isoforms to different subcellular compartments. PanK1α isoforms were exclusively nuclear, with preferential association with the granular component of the nucleolus during interphase. PanK1α also associated with the perichromosomal region in condensing chromosomes during mitosis. The PanK1β and PanK3 isoforms were cytosolic, with a portion of PanK1β associated with clathrin-associated vesicles and recycling endosomes. Human PanK2, known to associate with mitochondria, was specifically localized to the intermembrane space. Human PanK2 was also detected in the nucleus, and functional nuclear localization and export signals were identified and experimentally confirmed. Nuclear PanK2 trafficked from the nucleus to the mitochondria, but not in the other direction, and was absent from the nucleus during G2 phase of the cell cycle. The localization of human PanK2 in these two compartments was in sharp contrast to mouse PanK2, which was exclusively cytosolic. These data demonstrate that PanK isoforms are differentially compartmentalized allowing them to sense CoA homeostasis in different cellular compartments and enable interaction with regulatory ligands produced in these same locations.泛酸激酶（pantothenate kinases, PanK）催化辅酶A（coenzyme A, CoA）生物合成的第一步且为限速步骤，并通过差异同工型表达及与代谢配体的别构相互作用，调控组织内辅酶A的含量。人类与小鼠的四种PanK蛋白共享同源的羧基端催化结构域，但氨基端序列存在差异。这些独特的氨基端将不同的PanK同工型靶向至不同的亚细胞区室。PanK1α同工型仅定位于细胞核，在细胞间期优先结合于核仁的颗粒组分；在有丝分裂期，PanK1α还可结合于凝聚染色体的染色体周区域。PanK1β与PanK3同工型定位于胞质，其中部分PanK1β可结合于网格蛋白包被囊泡及循环内体。已知可定位于线粒体的人类PanK2，特异性定位于线粒体膜间隙。研究还在人类PanK2中检测到细胞核分布，且其相关的核定位与核输出信号已被实验验证。核内的PanK2可从细胞核转运至线粒体，但无法反向转运，且在细胞周期的G2期时细胞核内无PanK2分布。人类PanK2在这两个区室的定位模式，与仅定位于胞质的小鼠PanK2形成鲜明对比。上述数据表明，PanK同工型存在差异化的区室定位，这使得它们能够感知不同亚细胞区室的辅酶A稳态，并与对应区域产生的调控配体发生相互作用。