Nuclear trafficking of metallothionein: Possible mechanisms and current knowledge

Although metallothionein (MT) was first characterized as a cytoplasmic prot ein, it is now known to be localized in the nucleus depending on various ce llular events, such as cell proliferation. The suggested roles of karyophil ic MT are: to 1) regulate the biological pool of the essential metals zinc (Zn) and copper (Cu), and especially to supply Zn to Zn-requiring enzymes/t ranscription factors through activated cell proliferation, and 2) to protec t DNA from oxidative stress including those caused by antitumor agents. Tra nslocation of MT to the nucleus might be mediated, depending on cellular ev ents, by a structural change in MT itself or through the appearance of nucl ear binding proteins. Supporting the former possibility, MT is known to hav e some structural features, namely, highly conserved lysyl residues, which are anticipated to act as nuclear localization signal (NLS). In addition, c oncomitant appearance of non-acetylated MT, without post-translational acet ylation, and nuclear localization of MT, have been reported. Supporting the latter possibility, MT-partner proteins might participate in the nuclear t rafficking of MT (i.e., an MT-nuclear translocator or a nuclear chaperone o f MT). We now provide an overview of the current knowledge on both mechanis ms.