STUB1-mediated ubiquitination regulates the stability of GLUD1 in lung adenocarcinoma

Qifan Hu; Jiapeng Lei; Zhujun Cheng; Jing Xu; Lei Wang; Yi Yuan; Mingxi Gan; Yanan Wang; Yilin Xie; Lu Yao; Keru Wang; Yuhan Liu; Wenze Xun; Jian-Bin Wang; Tianyu Han

doi:10.1016/j.isci.2023.107151

STUB1-mediated ubiquitination regulates the stability of GLUD1 in lung adenocarcinoma

iScience. 2023 Jun 15;26(7):107151. doi: 10.1016/j.isci.2023.107151. eCollection 2023 Jul 21.

Authors

Qifan Hu^{1

2

3}, Jiapeng Lei^{2

4}, Zhujun Cheng⁵, Jing Xu², Lei Wang², Yi Yuan⁶, Mingxi Gan², Yanan Wang¹, Yilin Xie⁷, Lu Yao⁶, Keru Wang⁶, Yuhan Liu², Wenze Xun², Jian-Bin Wang^{2

3}, Tianyu Han^{1

8

9}

Affiliations

¹ Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi 330006, China.
² School of Basic Medical Sciences, Nanchang University, Nanchang City, Jiangxi 330031, China.
³ Department of Thoracic Surgery, The First Affifiliated Hospital of Nanchang University, Nanchang City, Jiangxi 330006, China.
⁴ School of Basic Medical Sciences, Nanchang Medical College, Nanchang City, Jiangxi 330000, China.
⁵ Department of Burn, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi 330006, China.
⁶ School of Huankui Academy, Nanchang University, Nanchang City, Jiangxi 330031, China.
⁷ School of Queen Mary, Nanchang University, Nanchang City, Jiangxi 330031, China.
⁸ Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang City, Jiangxi 330006, China.
⁹ China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang City, Jiangxi 330200, China.

Abstract

The dysregulation of glutamine metabolism provides survival advantages for tumors by supplementing tricarboxylic acid cycle. Glutamate dehydrogenase 1 (GLUD1) is one of the key enzymes in glutamine catabolism. Here, we found that enhanced protein stability was the key factor for the upregulation of GLUD1 in lung adenocarcinoma. We discovered that GLUD1 showed a high protein expression in lung adenocarcinoma cells or tissues. We elucidated that STIP1 homology and U-box-containing protein 1 (STUB1) was the key E3 ligase responsible for ubiquitin-mediated proteasomal degradation of GLUD1. We further showed that lysine 503 (K503) was the main ubiquitination site of GLUD1, inhibiting the ubiquitination at this site promoted the proliferation and tumor growth of lung adenocarcinoma cells. Taken together, this study clarifies the molecular mechanism of GLUD1 in maintaining protein homeostasis in lung adenocarcinoma, which provides a theoretical basis for the development of anti-cancer drugs targeting GLUD1.

Keywords: Biological sciences; Cancer; Cell biology; Molecular biology.