Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• 细胞研究：英文版, 2015 (9), p.1025-1042

Erscheinungsjahr

2015

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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.