Ware Adam W, Cheung Tanya T, Rasulov Sahib, Burstein Ezra, McDonald Fiona J
Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Department of Internal Medicine and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Front Physiol. 2018 Jun 26;9:793. doi: 10.3389/fphys.2018.00793. eCollection 2018.
Optimal function of the epithelial sodium channel (ENaC) in the distal nephron is key to the kidney's long-term control of salt homeostasis and blood pressure. Multiple pathways alter ENaC cell surface populations, including correct processing and trafficking in the secretory pathway to the cell surface, and retrieval from the cell surface through ubiquitination by the ubiquitin ligase Nedd4-2, clathrin-mediated endocytosis, and sorting in the endosomal system. Members of the Copper Metabolism Murr1 Domain containing (COMMD) family of 10 proteins are known to interact with ENaC. COMMD1, 3 and 9 have been shown to down-regulate ENaC, most likely through Nedd4-2, however, the other COMMD family members remain uncharacterized. To investigate the effects of the COMMD10 protein on ENaC trafficking and function, the interaction of ENaC and COMMD10 was confirmed. Stable COMMD10 knockdown in Fischer rat thyroid epithelia decreased ENaC current and this decreased current was associated with increased Nedd4-2 protein, a known negative regulator of ENaC. However, inhibition of Nedd4-2's ubiquitination of ENaC was only able to partially rescue the observed reduction in current. Stable COMMD10 knockdown results in defects both in endocytosis and recycling of transferrin suggesting COMMD10 likely interacts with multiple pathways to regulate ENaC and therefore could be involved in the long-term control of blood pressure.
远端肾单位中上皮钠通道（ENaC）的最佳功能是肾脏长期控制盐稳态和血压的关键。多种途径可改变ENaC的细胞表面数量，包括在分泌途径中正确加工和运输至细胞表面，以及通过泛素连接酶Nedd4-2进行泛素化、网格蛋白介导的内吞作用从细胞表面回收，以及在内体系统中进行分选。已知含铜代谢Murr1结构域（COMMD）的10种蛋白质家族成员与ENaC相互作用。已证明COMMD1、3和9可下调ENaC，最有可能是通过Nedd4-2，但其他COMMD家族成员仍未被研究。为了研究COMMD10蛋白对ENaC运输和功能的影响，证实了ENaC与COMMD10的相互作用。在Fischer大鼠甲状腺上皮细胞中稳定敲低COMMD10可降低ENaC电流，而这种电流降低与ENaC的已知负调节因子Nedd4-2蛋白增加有关。然而，抑制Nedd4-2对ENaC的泛素化仅能部分挽救观察到的电流降低。稳定敲低COMMD10会导致转铁蛋白内吞和再循环出现缺陷，这表明COMMD10可能与多种途径相互作用以调节ENaC，因此可能参与血压的长期控制。
