Abstract
PTEN tumor suppressor opposes the PI3K/Akt signaling pathway in the cytoplasm and maintains chromosomal integrity in the nucleus. Nucleus–cytoplasm shuttling of PTEN is regulated by ubiquitylation, SUMOylation and phosphorylation, and nuclear PTEN has been proposed to exhibit tumor-suppressive functions. Here we show that PTEN is conjugated by Nedd8 under high glucose conditions, which induces PTEN nuclear import without effects on PTEN stability. PTEN neddylation is promoted by the XIAP ligase and removed by the NEDP1 deneddylase. We identify Lys197 and Lys402 as major neddylation sites on PTEN. Neddylated PTEN accumulates predominantly in the nucleus and promotes rather than suppresses cell proliferation and metabolism. The nuclear neddylated PTEN dephosphorylates the fatty acid synthase (FASN) protein, inhibits the TRIM21-mediated ubiquitylation and degradation of FASN, and then promotes de novo fatty acid synthesis. In human breast cancer tissues, neddylated PTEN correlates with tumor progression and poor prognosis. Therefore, we demonstrate a previously unidentified pool of nuclear PTEN in the Nedd8-conjugated form and an unexpected tumor-promoting role of neddylated PTEN.
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Data availability
For IP-MS, all raw data and search results have been deposited to the PRIDE database (http://www.iprox.org/index) with the accession number: PXD011368 (Supplementary information, Data S1); PXD021544 (Supplementary information, Data S2); PXD011395 (Supplementary information, Data S3). The authors declare that all the relevant data supporting the findings of this study are available within the article and its Supplementary information files, or from the corresponding author on reasonable request.
Change history
29 January 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41422-021-00470-4
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Acknowledgements
We thank Drs. Mian Wu (University of Science and Technology of China, Anhui Province, China), Xiaofeng Zheng (Peking University, Beijing, China), Mingyao Liu (East China Normal University, Shanghai, China), Qinong Ye (Beijing Institute of Biotechnology) for kindly providing materials. This work was jointly supported by the National Key R&D Program of China (2017YFA0505602), Chinese National Basic Research Programs (2015CB910401), Chinese National Natural Science Foundation Project (31670774, 31971229), Beijing Natural Science Foundation Project (Z151100003915083), Open Project Program of the State Key Laboratory of Proteomics (SKLP-O201901), Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan (CIT&TCD201704097) and Beijing excellent talents training project.
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The project was conceived by L.Z. The experiments were designed by L.Z., P.X. and F.H. Most of the modification experiments were performed by P.X. The cell biology function experiments were contributed by Z.P., P.X., and M.D. The animal experiments were contributed by Z.P., H.L. and X.Z. The breast cancer sample collection and immunohistochemical analysis were contributed by Z.P., Y.C. and Y.T. The statistical analysis was completed by Z.P., Z.L., C.H.L. and C.-P.C. Data were analyzed by L.Z., P.X. and Z.P. The manuscript was written by L.Z. and P.X.
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Xie, P., Peng, Z., Chen, Y. et al. Neddylation of PTEN regulates its nuclear import and promotes tumor development. Cell Res 31, 291–311 (2021). https://doi.org/10.1038/s41422-020-00443-z
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DOI: https://doi.org/10.1038/s41422-020-00443-z
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