Three Distinct Domains Contribute to Nuclear Transport of Murine Foxp3Report as inadecuate




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Foxp3, a 47-kDa transcription factor, is necessary for the function of CD4+CD25+ regulatory T cells Tregs, with an essential role in the control of self-reactive T cells and in preventing autoimmunity. Activation of Tregs by TCR engagement results in upregulation of Foxp3 expression, followed by its rapid nuclear transport and binding to chromatin. Here, we identify three distinct Foxp3 domains that contribute to nuclear transport. The first domain Domain 1 comprises the C-terminal 12 amino acids. The second domain Domain 2 is located immediately N-terminal to the forkhead domain FHD, recently reported to be a binding site for the runt-related transcription factor 1-acute myeloid leukemia 1 Runx1-AML1. The third domain Domain 3 is located within the N-terminal first 51 amino acids. Unlike the known nuclear localization signals NLSs, none of these three regions are rich in basic residues and do not bear any similarity to known monopartite or bipartite NLSs that have one or more clusters of basic amino acids. The basic arginine-lysine-lysine-arginine RKKR sequence, located 12-aa from the C-terminal end of Foxp3 was previously reported to be a nuclear localization signal NLS for several proteins, including for a GFP-Foxp3 hybrid. Evidence is provided here that in the full-length native Foxp3 RKKR does not function as an NLS. The data reported in this study indicates that Foxp3 achieves nuclear transport by binding to other nuclear factors and co-transporting with them to the nucleus.



Author: Wayne W. Hancock, Engin Özkaynak

Source: http://plos.srce.hr/



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