Volume 31, No 3, Mar 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 3, March 2021: 291-311

ORIGINAL ARTICLES

Neddylation of PTEN regulates its nuclear import and promotes tumor development

Ping Xie^1,* , Zhiqiang Peng² , Yujiao Chen¹ , Hongchang Li² , Mengge Du¹ , Yawen Tan³ , Xin Zhang² , Zhe Lu⁴ , Chun-Ping Cui² , Cui Hua Liu⁴ , Fuchu He² , Lingqiang Zhang^2,*

¹Department of Cell Biology, The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
²State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
³Department of Breast and Thyroid Surgery, The Second People’s Hospital of Shenzhen, Shenzhen, Guangdong 518035, China
⁴CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology (Chinese Academy of Sciences), Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100101, China
These authors contributed equally: Ping Xie, Zhiqiang Peng Correspondence: Ping Xie(xiep@ccmu.edu.cn)Lingqiang Zhang(zhanglq@nic.bmi.ac.cn)

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.

https://doi.org/10.1038/s41422-020-00443-z

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