Nuclear trafficking of metallothionein: possible mechanisms and current knowledge

Although metallothionein (MT) was first characterized as a cytoplasmic protein, it is now known to be localized in the nucleus depending on various cellular events, such as cell proliferation. The suggested roles of karyophilic 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/transcription factors through activated cell proliferation, and 2) to protect DNA from oxidative stress including those caused by antitumor agents. Translocation of MT to the nucleus might be mediated, depending on cellular events, by a structural change in MT itself or through the appearance of nuclear binding proteins. Supporting the former possibility, MT is known to have some structural features, namely, highly conserved lysyl residues, which are anticipated to act as nuclear localization signal (NLS). In addition, concomitant appearance of non-acetylated MT, without post-translational acetylation, and nuclear localization of MT, have been reported. Supporting the latter possibility, MT-partner proteins might participate in the nuclear trafficking of MT (i.e., an MT-nuclear translocator or a nuclear chaperone of MT). We now provide an overview of the current knowledge on both mechanisms.