COMMD1 and ion transport proteins: what is the COMMection? Focus on "COMMD1 interacts with the COOH terminus of NKCC1 in Calu-3 airway epithelial cells to modulate NKCC1 ubiquitination".

OVER THE PAST DECADE, COMMD1 (copper metabolism MURR1 domain containing protein 1) has been regularly identified to interact with ion transport proteins. What do we know about COMMD1, and is there a common ion transport regulatory role for COMMD1? COMMD1 is evolutionarily conserved, and codes for a 21-kDa protein composed of two domains: a COOH-terminal COMM domain found in nine other COMMD proteins, and a nonconserved NH2-terminal domain (6). COMMD1 has a wide tissue expression pattern, is located in the cytosol and nucleus, and colocalizes with early and late endosomal markers (2–4), maybe through interaction with phosphatidylinositol 4,5-bisphosphate (2). COMMD1 has no known enzymatic function and is hypothesized to be an adaptor or scaffold protein. Initially, COMMD1 was reported to regulate copper transport after dogs suffering from liver copper toxicosis were found to have COMMD1 loss of function mutations (11). Although COMMD1 genetic variations are not linked to human copper overload disorders, COMMD1 does interact with the ATP7A and ATP7B copper transporters, which contain mutations in human copper deficiency or overload diseases (8). COMMD1 was identified through a yeast two-hybrid screen to interact with the -subunit of the epithelial sodium channel (ENaC) and subsequently three other ENaC subunits ( ) (1, 5). Although the in vivo function of ENaC is unknown, the ENaC channel forms an aldosterone-induced, amiloridesensitive apically located Na absorption pathway in distal epithelia. Specific mutations in ENaC genes cause hypoor hypertension through alteration of distal nephron Na absorption. The cystic fibrosis transmembrane conductance regulator (CFTR) is also located in epithelia and forms an apically located Cl and HCO3 secretion pathway, which is attenuated when CFTR contains mutations causing cystic fibrosis leading to multiple symptoms including respiratory dysfunction. In the lung, Na absorption and Cl secretion pathways may be coregulated; therefore it was interesting that COMMD1 was also found to interact with CFTR via a two-hybrid screen (4). Figure 1 depicts a hypothetical cell showing the locations of COMMD1-regulated ion transport proteins. In this issue of American Journal of Physiology-Cell Physiology, Smith et al. (9) report the Na-K-2Cl cotransporter 1 (NKCC1) as another COMMD1-regulated ion transporter. NKCC1 has a general role in cell volume regulation and specific roles in epithelial Cl secretion and vestibular function. Smith et al. report that a yeast two-hybrid screen with the cytoplasmic COOH-terminal region of NKCC1 bound COMMD1, and that the NH2-terminal domain of COMMD1 interacts with NKCC1. A COMMD1 1–47 amino acid peptide was sufficient to both stabilize NKCC1 at the cell surface of Calu-3 airway epithelial cells and increase baseline bumetanide-sensitive Rb uptake, indicative of NKCC1 activity. In contrast, transient knockdown of COMMD1 in Calu-3 cells did not alter baseline or sucrose-induced activation of NKCC1 activity, but resulted in reduced basolateral NKCC1 and prevented a sucrose-induced transient increase in basolateral NKCC1 population, suggesting a complex regulation of NKCC1 by COMMD1. COMMD1 has a wider role in cellular physiology as it interacts with NFB and HIF-1 transcription factors, HSP70, and proteins in the DNA damage response network (6, 10). What is the link between COMMD1 and this diverse range of proteins? At present, COMMD1’s ability to alter protein stability is the best candidate for a universal COMMD1 function. Extensive study in the NFB pathway showed that COMMD1 promotes ubiquitination of NFB subunits, thus targeting NFB for degradation and decreasing NFB-mediated tran-