Volume 25, No 9, Sep 2015

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

Volume 25 Issue 9, September 2015: 1025-1042   |  Open Access

ORIGINAL ARTICLES

RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect

Chen-Song Zhang^1,*, Qi Liu^1,*, Mengqi Li^1,*, Shu-Yong Lin^1,*, Yongying Peng¹, Di Wu¹, Terytty Yang Li¹, Qiang Fu², Weiping Jia³, Xinjun Wang⁴, Teng Ma¹, Yue Zong¹, Jiwen Cui¹, Chengfei Pu¹, Guili Lian¹, Huiling Guo¹, Zhiyun Ye¹ and Sheng-Cai Lin¹

¹State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China
²Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
³Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
⁴Department of Urology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China Correspondence: Sheng-Cai Lin, Tel: +86 592 218 2993; Fax: +86 592 218 2993(linsc@xmu.edu.cn)

Hypoxia-inducible factors (HIFs) are master regulators of adaptive responses to low oxygen, and their α-subunits are rapidly degraded through the ubiquitination-dependent proteasomal pathway after hydroxylation. Aberrant accumulation or activation of HIFs is closely linked to many types of cancer. However, how hydroxylation of HIFα and its delivery to the ubiquitination machinery are regulated remains unclear. Here we show that Rho-related BTB domain-containing protein 3 (RHOBTB3) directly interacts with the hydroxylase PHD2 to promote HIFα hydroxylation. RHOBTB3 also directly interacts with the von Hippel-Lindau (VHL) protein, a component of the E3 ubiquitin ligase complex, facilitating ubiquitination of HIFα. Remarkably, RHOBTB3 dimerizes with LIMD1, and constructs a RHOBTB3/LIMD1-PHD2-VHL-HIFα complex to effect the maximal degradation of HIFα. Hypoxia reduces the RHOBTB3-centered complex formation, resulting in an accumulation of HIFα. Importantly, the expression level of RHOBTB3 is greatly reduced in human renal carcinomas, and RHOBTB3 deficiency significantly elevates the Warburg effect and accelerates xenograft growth. Our work thus reveals that RHOBTB3 serves as a scaffold to organize a multi-subunit complex that promotes the hydroxylation, ubiquitination and degradation of HIFα.

10.1038/cr.2015.90

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