CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain

RNA editing of specific residues by adenosine deamination is a nuclear proc ess catalyzed by adenosine deaminases acting on RNA (ADAR). Different promo ters in the ADAR1 gene give rise to two forms of the protein: a constitutiv e promoter expresses a transcript encoding (c)ADAR1, and an interferon-indu ced promoter expresses a transcript encoding an N-terminally extended form, (i)ADAR1. Here we show that (c)ADAR1 is primarily nuclear whereas (i)ADAR1 encompasses a functional nuclear export signal in the N-terminal part and is a nucleocytoplasmic shuttle protein. Mutation of the nuclear export sign al or treatment with the CRM1-specific drug leptomycin B induces nuclear ac cumulation of (i)ADAR1 fused to the green fluorescent protein and increases the nuclear editing activity. In concurrence, CRM1 and RanGTP interact spe cifically with the (i)ADAR1 nuclear export signal to form a tripartite expo rt complex in vitro. Furthermore, our data imply that nuclear import of (i) ADAR1 is mediated by at least two nuclear localization sequences. These res ults suggest that the nuclear editing activity of (i)ADAR1 is modulated by nuclear export.