The RanBP2/RanGAP1-SUMO complex gates beta-arrestin2 nuclear entry to regulate the Mdm2-p53 signaling axis

Mdm2 antagonizes the tumor suppressor p53. Targeting the Mdm2-p53 interaction represents an attractive approach for the treatment of cancers with functional p53. Investigating mechanisms underlying Mdm2-p53 regulation is therefore important. The scaffold protein beta-arrestin2 (beta-arr2) regulates tumor suppressor p53 by counteracting Mdm2.beta-arr2 nucleocytoplasmic shuttling displaces Mdm2 from the nucleus to the cytoplasm resulting in enhanced p53 signaling. beta-arr2 is constitutively exported from the nucleus, via a nuclear export signal, but mechanisms regulating its nuclear entry are not completely elucidated. beta-arr2 can be SUMOylated, but no information is available on how SUMO may regulate beta-arr2 nucleocytoplasmic shuttling. While we found beta-arr2 SUMOylation to be dispensable for nuclear import, we identified a non-covalent interaction between SUMO and beta-arr2, via a SUMO interaction motif (SIM), that is required for beta-arr2 cytonuclear trafficking. This SIM promotes association of beta-arr2 with the multimolecular RanBP2/RanGAP1-SUMO nucleocytoplasmic transport hub that resides on the cytoplasmic filaments of the nuclear pore complex. Depletion of RanBP2/RanGAP1-SUMO levels result in defective beta-arr2 nuclear entry. Mutation of the SIM inhibits beta-arr2 nuclear import, its ability to delocalize Mdm2 from the nucleus to the cytoplasm and enhanced p53 signaling in lung and breast tumor cell lines. Thus, a beta-arr2 SIM nuclear entry checkpoint, coupled with active beta-arr2 nuclear export, regulates its cytonuclear trafficking function to control the Mdm2-p53 signaling axis.