- Elongin C is a small adaptor protein that functions as a core component of several multiprotein complexes involved in transcriptional regulation and protein ubiquitination.
- It is encoded by the ELOC gene and belongs to the Skp1 family of adaptor proteins, which are structurally designed to connect substrate-binding proteins with scaffold proteins in ubiquitin ligase assemblies.
- Elongin C is best known for forming a stable heterodimer with elongin B, a ubiquitin-like protein, and together they act as a structural platform for binding elongin A or other substrate recognition proteins. This arrangement allows elongin C to serve as a molecular bridge, linking regulatory subunits to functional enzymatic machinery in different biological pathways.
- One of the primary roles of elongin C is within the Elongin complex, consisting of elongin A, B, and C. In this complex, elongin A acts as the catalytic subunit that enhances RNA polymerase II transcription elongation, while elongins B and C form a dimer that stabilizes elongin A and ensures the integrity of the complex. By preventing RNA polymerase II pausing, the Elongin complex facilitates efficient gene transcription, particularly in genes that require rapid and continuous expression. Elongin C’s role as an adaptor ensures that elongin A is properly anchored and regulated, making it essential for transcriptional productivity.
- Beyond transcription, elongin C plays a central role in protein ubiquitination as part of the von Hippel–Lindau (VHL) E3 ubiquitin ligase complex. In this setting, elongin C, in partnership with elongin B, binds to the VHL tumor suppressor protein and connects it to the Cullin-2 scaffold. Together with Rbx1, this forms the VBC-CUL2-Rbx1 ligase complex, which ubiquitinates hypoxia-inducible factor alpha (HIF-α) under normoxic conditions, targeting it for proteasomal degradation. Through this function, elongin C contributes to the cellular oxygen-sensing pathway, regulating angiogenesis, erythropoiesis, and metabolism. Importantly, disruption of this pathway—often due to mutations in VHL—leads to inappropriate stabilization of HIF-α and is a hallmark of clear cell renal cell carcinoma and other VHL-associated tumors. Although elongin C itself is rarely mutated, its role is indispensable for the stability and activity of this tumor-suppressive complex.
- Structurally, elongin C resembles Skp1 in its ability to interact with both substrate-recognition proteins and Cullin family scaffolds. This allows elongin C to function as a flexible adaptor, making it a shared component across different protein complexes. Its capacity to stabilize and bridge interactions explains its dual roles in transcriptional regulation and protein ubiquitination, processes that together ensure proper control of gene expression and protein homeostasis.
- From a biomedical standpoint, elongin C is significant due to its role in the VHL tumor suppressor pathway. While it does not act as a tumor suppressor itself, its function is critical for enabling VHL to regulate HIF-α degradation. Consequently, any disruption in elongin C expression or function would impair oxygen homeostasis and potentially contribute to disease. Beyond cancer, its function in transcription elongation may also influence stress responses, developmental gene expression, and cellular adaptation, although these roles are less well studied compared to its involvement in the ubiquitin ligase complex.
