A Novel Post-Translational Modification of Nucleolin, SUMOylation at K294, Mediates Arsenite-induced Cell Death by Regulating gadd45a mRNA Stability [Cell Biology]

January 5th, 2015 by Zhang, D., Liang, Y., Xie, Q., Gao, G., Wei, J., Huang, H., Li, J., Gao, J., Huang, C.

Nucleolin is a ubiquitously expressed protein and participates in many important biological processes, such as cell cycle regulation and ribosomal biogenesis. The activity of nucleolin is regulated by intracellular localization and post-translational modifications (PTMs), including phosphorylation, methylation and ADP-ribosylation. Small ubiquitin-like modifier (SUMO) is a category of lately verified forms of PTMs, and exerts various effects on the target proteins. In the studies reported here, we discovered SUMOylational modification of human nucleolin protein at K294, which facilitated the mRNA binding property of nucleolin by maintaining its nucleus localization. In response to arsenic exposure, nucleolin-SUMO was induced and promoted its binding with gadd45a mRNA, which increased gadd45a mRNA stability and protein expression, subsequently causing GADD45α-mediated cell death. On the other hand, ectopic expression of MnSOD attenuated arsenite-generated superoxide radical level, abrogated nucleolin-SUMO, and in turn inhibited arsenite-induced apoptosis by reducing GADD45α expression. Collectively, our results for the first time demonstrated that nucleolin-SUMO at K294R played a critical role in its nucleus sequestration and gadd45a mRNA binding activity. This novel biological function of nucleolin was distinct from its conventional role as proto-oncogene. Therefore, our findings here not only discovered a new modification of nucleolin protein and its novel functional paradigm in mRNA metabolism, but also expanded our understanding regarding the dichotomous roles of nucleolin in term of cancer development, which were dependent on multiple intracellular conditions, and consequently the appropriate regulations of its modifications, including SUMOylation.
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