- The VBC complex—composed of von Hippel–Lindau protein (pVHL), elongin B, and elongin C—is a multiprotein assembly that plays a pivotal role in cellular oxygen sensing, transcriptional regulation, and tumor suppression.
- It was first identified in studies of the VHL tumor suppressor gene, mutations of which underlie von Hippel–Lindau disease, a hereditary cancer syndrome characterized by highly vascular tumors such as hemangioblastomas, clear cell renal cell carcinomas, and pheochromocytomas. The VBC complex represents the functional form of pVHL in cells, and its activity centers on ubiquitin-mediated proteolysis of key regulatory proteins, most notably hypoxia-inducible factor alpha (HIF-α).
- Structurally, the VBC complex consists of three tightly associated components. pVHL serves as the substrate-recognition subunit, binding specifically to HIF-α when it is hydroxylated on conserved proline residues under normoxic conditions. Elongin C, a Skp1-like adaptor protein, provides a bridge between pVHL and Cullin-2, while elongin B, a ubiquitin-like protein, stabilizes elongin C and helps maintain the integrity of the complex. Together, elongin B and C form a stable heterodimer that docks onto pVHL, thereby creating the VBC complex. This trimer can then associate with Cullin-2 and Rbx1 to form the complete Cullin–RING E3 ubiquitin ligase, often referred to as the VCB–Cullin-2–Rbx1 complex.
- The primary biological role of the VBC complex is to regulate the degradation of HIF-α subunits, which control the transcriptional response to oxygen availability. Under normal oxygen conditions, prolyl hydroxylase domain proteins (PHDs) hydroxylate HIF-α at specific residues within its oxygen-dependent degradation domain (ODD). Hydroxylated HIF-α is recognized and bound by pVHL within the VBC complex. Once bound, the VBC complex, through its association with Cullin-2 and Rbx1, recruits an E2 ubiquitin-conjugating enzyme, which transfers ubiquitin molecules to HIF-α, marking it for rapid degradation by the proteasome. Under hypoxic conditions, hydroxylation is inhibited, HIF-α escapes recognition by pVHL, and the VBC complex cannot target it for degradation—allowing HIF-α to accumulate, translocate into the nucleus, and activate hypoxia-responsive genes.
- Beyond HIF regulation, the VBC complex has additional cellular functions. pVHL has been implicated in the regulation of microtubule stability, extracellular matrix deposition, and maintenance of primary cilia, although many of these roles are carried out in cooperation with elongins B and C. The complex has also been suggested to contribute to transcriptional elongation through its evolutionary link to the Elongin complex, which promotes RNA polymerase II activity. Thus, the VBC complex is not only critical for oxygen sensing but also participates in broader aspects of cell physiology.
- Clinically, the importance of the VBC complex lies in its tumor suppressor function. Mutations or inactivation of pVHL disrupt the ability of the VBC complex to recognize and degrade HIF-α, leading to chronic stabilization of HIF-α even under normoxic conditions. This aberrant activation of hypoxia signaling drives uncontrolled angiogenesis, metabolic reprogramming, and tumor growth, especially in clear cell renal cell carcinoma. Although elongins B and C are rarely mutated in cancer, their structural role in stabilizing pVHL means they are indispensable for tumor suppression.
