Endocytic control of cell-autonomous and non-cell-autonomous functions of p53

NUMB is an endocytic protein with tumor suppressor activity, largely mediated by its ability to inhibit p53 degradation. This function depends on the inclusion of a short alternatively spliced exon (Ex3) in NUMB, although the mechanistic link between endocytosis and p53 regulation remains unclear. Here, we show that the Ex3-encoded sequence directs NUMB to the plasma membrane, where it forms a complex with the endocytic adaptor SNX9. This complex recruits p53 in a SNX9-dependent manner and is internalized and trafficked to multivesicular bodies, culminating in exosomal secretion, in a process requiring both SNX9 and NUMB. Exosomal p53 is taken up by recipient cells and translocated to the nucleus, where it activates p53-dependent transcriptional and phenotypic programs. These findings suggest that exosome-mediated p53 transfer may contribute to the establishment of a tumor-suppressive microenvironment.