COMMD1: A Multifunctional Regulatory Protein

Abstract

The COMMD Protein Family is highly conserved among multicellular eukaryotic organisms and many orthologs of human COMMD genes have been found in different species of plants, invertebrates, lower vertebrates, and mammals. COMMD1 is the best characterized member of the family and is conserved among vertebrates. This protein represents a pleiotropic factor involved in the regulation of many cellular and physiological processes that include copper and cholesterol homeostasis, ionic transport, oxidative stress, protein aggregation, protein trafficking, NF-kB-mediated transcription, hypoxia induced transcription, DNA damage response, and oncogenesis. The present work reviews the molecular mechanisms and biological processes regulated by COMMD1 that have been described so far, emphasizing in the regulatory role of the protein and its importance for cellular homeostasis. J. Cell. Biochem. 119: 34-51, 2018. © 2017 KEY WORDS: COMMD1; COPPER METABOLISM; PROTEIN TRAFFICKING; IONIC TRANSPORT; TRANSCRIPTION REGULATION; ONCOGENESIS P rotein-Protein interactions (PPI) are crucial for the majority of biological processes, including macromolecular assemblies, enzymatic complexes, mitogenic events, signal transduction, metabolism, and regulation pathways [Li et al., 2004;Lev et al., 2013]. The identification of binding partners for particular proteins and the establishment of protein-protein networks are critical to comprehend many cellular and physiological functions [Moreira et al., 2007]. These studies are also important for drug design and discovery of novel molecular targets, with biological and clinical significance in the treatment of diverse pathologies [Cukuroglu et al., 2014].The COMMD (Copper Metabolism MURR1 Domain-containing) Protein Family, highly conserved in eukaryotic multicellular organisms, is implicated in the regulation of many biological processes through PPI [Bartuzi et al., 2013]. The specific functions of COMMD proteins are not defined, but they have been connected to the regulation of transcription factors like NF-kB [Ganesh et al., 2003;Burstein et al., 2005;de Bie et al., 2006]. Besides, some of these proteins are strongly suppressed in tumor cells, a finding that suggests antitumor activity [reviewed in Burstein et al., 2005]. COMMD1 is the best characterized member of the family and several partners have been known to interact with this protein [Vonk et al., 2010]. COMMD1 is implicated in many different cellular functions, such as copper balance, cholesterol homeostasis, ionic transport, transcription regulation, and oxidative stress [Vonk et al., 2010;Mao et al., 2011;Bartuzi et al., 2016]. Thus, it represents a pleiotropic factor essential for cellular homeostasis and a molecular target for modulation/disruption of pathological events. The current review describes the molecular mechanisms and biological processes regulated by COMMD1 that have been reported to date, emphasizing in the regulatory role of the protein and its implication in cellular homeostasis. COMMD PROTEIN FAMILY EVOLUTIONARY...

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