Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2

Abstract

<jats:p>The stringent expression of the hypoxia inducible factor-1α (HIF-1α) is critical to a variety of pathophysiological conditions. We reveal that, in normoxia, enzymatic action of cystathionine β-synthase (CBS) produces H<jats:sub>2</jats:sub>S, which persulfidates prolyl hydroxylase 2 (PHD2) at residues Cys<jats:sup>21</jats:sup> and Cys<jats:sup>33</jats:sup> (zinc finger motif), augmenting prolyl hydroxylase activity. Depleting endogenous H<jats:sub>2</jats:sub>S either by hypoxia or by inhibiting CBS via chemical or genetic means reduces persulfidation of PHD2 and inhibits activity, preventing hydroxylation of HIF-1α, resulting in stabilization. Our in vitro findings are further supported by the depletion of CBS in the zebrafish model that exhibits axis defects and abnormal intersegmental vessels. Exogenous H<jats:sub>2</jats:sub>S supplementation rescues both in vitro and in vivo phenotypes. We have identified the persulfidated residues and defined their functional significance in regulating the activity of PHD2 via point mutations. Thus, the CBS/H<jats:sub>2</jats:sub>S/PHD2 axis may provide therapeutic opportunities for pathologies associated with HIF-1α dysregulation in chronic diseases.</jats:p>

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

“…Taking these observations into account, we propose that the elevated levels of CBS in BLBC could, instead, drive HIF-PH2 inactivation via persulfidation of specific Cys residues. Notwithstanding, in stark contrast to this hypothesis and our observation that CBS knockdown strongly abrogated the HIF1-α response to hypoxia, a recent study on HUVEC and HAoEC endothelial cells found that CBS inhibition stabilized HIF1-α via protecting HIF-PH2 through persulfidation of specific zinc finger domain Cys residues ( 57 ). The authors suggested that exogenous administration of H 2 S or GYY4137 (a common H 2 S donor compound) could rescue CBS inhibition–induced HIF1-α stabilization.…”

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor

“…Persulfidation of PHD2 at cysteine residues located in its zinc finger domain augments the interaction between PHD2 and HIF-1α, thereby promoting HIF-1α hydroxylation and degradation [ 68 ]. Treatment with GYY4137, a slow-releasing H 2 S donor, was shown to partially reverse the hypoxia-induced increase in HIF-1α protein levels and was also found to have anticancer effects in several cancer cell lines [ 68 , 69 ]. Experiments in mouse xenograft models showed that GYY4137 decreased tumor sizes without affecting the body weight or behavior of mice [ 69 ].…”

Harnessing the Benefits of Endogenous Hydrogen Sulfide to Reduce Cardiovascular Disease

“…Hypoxia-inducible factor (HIF)-1α is an essential transcription factor that stimulates the expression of glycolytic genes in response to hypoxia or oxidation [ 99 ]. Under normoxic conditions, CBS-dependent H 2 S inhibits prolyl hydroxylase 2, which helps target HIF-1α for degradation, thus allowing HIF-1α to accumulate and induce gene expression [ 100 , 101 ]. These important proteins regulate the expression of metabolic genes demonstrating that H 2 S can even regulate metabolism at the transcriptional level.…”