Von Hippel-Lindau disease tumor suppressor (VHL)

The E3 ubiquitin-protein ligase VHL, also known as pVHL, is the substrate-recognition subunit of the Cullin-RING E3 ubiquitin ligase complex (CRL2-VHL) [1, 2]. Its most prominent biological role is the oxygen-dependent degradation of hypoxia-inducible factors (HIF-1α and HIF-2α), which are master transcription factors controlling the cellular response to low oxygen levels [1, 4]. Under normal oxygen conditions, VHL binds to prolyl-hydroxylated HIF-α and targets it for polyubiquitination and subsequent proteasomal degradation; however, in hypoxic environments or due to VHL mutations, HIF accumulates and triggers the expression of genes involved in angiogenesis, erythropoiesis, and glucose metabolism [4, 6]. Clinically, germline mutations in the VHL gene cause Von Hippel-Lindau syndrome, characterized by a predisposition to various tumors including clear cell renal cell carcinoma (ccRCC), hemangioblastomas, and pheochromocytomas [1, 7]. In drug discovery, VHL has become a cornerstone of targeted protein degradation (TPD), where small-molecule VHL ligands are used to construct Proteolysis-Targeting Chimeras (PROTACs) that hijack the ligase to selectively degrade disease-causing proteins [2, 11]. Furthermore, small-molecule inhibitors that disrupt the VHL-HIF interaction are under investigation as potential treatments for anemia and ischemia by stabilizing HIF to boost endogenous erythropoietin production [4, 16].

Other names

pVHLVon Hippel-Lindau proteinVHL1RCA1HRCA1Protein G7

E3 ligase recruitment for targeted protein degradation (via PROTACs); Competitive inhibition of VHL-HIF interaction to stabilize hypoxia-inducible factors [1, 4, 11].