Cytoplasmic sequestration of wild-type p53, representing a nonmutational event of p53 activity suppression, is a characteristic phenotype of undifferentiated neuroblastoma (NB); however, the underlying mechanism is yet to be defined. In the present study, we observed that TSPYL5 effectively tethers p53 in the cytoplasm and greatly inhibits its function as a transcription factor. Mechanistically, the binding of TSPYL5 with G3BP1 enhances G3BP1 Ser149 phosphorylation to drive G3BP1 nuclear membrane translocation, which recruits more p53 for nucleoporin RanBP2 by the formation of the RanBP2-G3BP1-p53 complex. Thus, the accelerating p53 sumoylation promotes its nuclear export. With this signal pathway, TSPYL5 augments the malignant characteristics of neuroblastoma cells. Our findings unravel a detailed TSPYL5-driven molecular axis that sheds light on the regulating system of the p53 sumoylation-based cytoplasmic sequestration in NB cells, paving the way for the novel therapeutic opportunities for NB cancers by antagonizing TSPYL5 function.
© 2025. The Author(s).