Identification of a novel nucleolar localization signal and a degradation signal in Survivin-deltaEx3: a potential link between nucleolus and protein degradation

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Abstract
For a long time, as the most prominent subnuclear structure, nucleolus has been recognized as a main site where rRNA processing and ribosomal subunit assemblies take place. It has not been until recently that additional functions of nucleolus have begun to be proposed. In this study, we for the first time demonstrate that Survivin-deltaEx3, a novel functionally splice variant of Survivin localizes in the nucleoli where it degrades rapidly through ubiquitin–proteosome pathway. Several lines of evidences provided in this report support this finding (i) a novel nucleolar localization sequence (NoLS, MQRKPTIRRKNLRLRRK) and a novel degradation signal (aa92–aa137) within Survivin-deltaEx3 were identified (ii) proteasome inhibitors MG132 or ALLN greatly inhibits degradation of Survivin-deltaEx3 and polyubiquitination of Survivin-deltaEx3 was detected (iii) heterologous proteins such as TAT-PTD or p14ARF, when fused to this putative degradation signal, result in a significant degradation within the nucleolus. In addition, the nucleolar localization and degradation of Survivin-deltaEx3 appear to be required for its antiapoptotic function, since neither NoLS-deleted nor degradation signal-deleted Survivin-deltaEx3 retains protective effect against Doxorubicin-induced apoptosis. Thus, our results have provided evidences to suggest that besides cytosol, nucleus, endoplsmic reticulum (ER) or lysosomes, nucleolus may also operate important protein degradation pathway, which has been overlooked previously.