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) regula...

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Bibliographic Details
Published in:Oncogene 2021, Vol.40 (12), p.2243
Main Authors: Blondel-Tepaz, Elodie, Leverve, Marie, Sokrat, Badr, Paradis, Justine S, Kosic, Milena, Saha, Kusumika, Auffray, Cédric
Format: Report
Language:English
Subjects:
Binding proteins
Carcinogenesis
Genetic aspects
Health aspects
Physiological aspects
Proto-oncogenes
Tumor suppressor genes
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Summary: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.
ISSN:0950-9232
DOI:10.1038/s41388-021-01704-w