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

作　　者：Chen-Song Zhang Qi Liu Mengqi Li Shu-Yong Lin Yongying Peng Di Wu Terytty Yang Li Qiang Fu Weiping Jia Xinjun Wang Teng Ma Yue Zong Jiwen Cui Chengfei Pu Guili Lian Huiling Guo Zhiyun Ye Sheng-Cai Lin 

机构地区：[1]State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China [2]Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China [3]Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China [4]Department of Urology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China

出　　处：《Cell Research》2015年第9期1025-1042,共18页细胞研究（英文版）

摘　　要：Hypoxia-inducible factors （HIFs） are master regulators of adaptive responses to low oxygen, and their a-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 HIFa 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 HIFa hydroxyl- ation. RHOBTB3 also directly interacts with the von Hippel-Lindau （VHL） protein, a component of the E3 ubiquitin ligase complex, facilitating ubiquitination of HIFa. Remarkably, RHOBTB3 dimerizes with LIMD1, and constructs a RHOBTB3/LIMD1-PHD2-VHL-HIFa complex to effect the maximal degradation of HIFa. Hypoxia reduces the RHOBTB3-centered complex formation, resulting in an accumulation of HIFa. 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 muiti-subunit complex that promotes the hydroxylation, ubiquitination and degradation of HIFa.

关 键 词：RHOBTB3 HIF PHD VHL HYDROXYLATION UBIQUITINATION the Warburg effect 

分 类 号：X592[环境科学与工程—环境工程] Q55[生物学—生物化学]