RHOBTB3 promotes proteasomal degradation of HIF? through facilitating hydroxylation and suppresses the Warburg effect.

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

SUBMITTER: Zhang CS 

PROVIDER: S-EPMC4559813 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature