The VHL short variant involves in protein quality control

•VHLs associated with ribosome via direct interaction with RPL6.•Manipulation of VHLs expression significantly impacts cell size, intracellular protein content and mitochondrial mass.•The expression of VHLs contributes to the robustness of translation process.•VHLs directly ubiquitinates the nascent peptides.•VHLs tightly associate with proteasome complex and involves in quality control of newly synthesized polypeptides during translation.

The von Hippel-Lindau (VHL) is the most important and frequently mutated gene in human clear cell renal cell carcinoma (ccRCC). In contrast to its long counterpart, the internal translational variant of VHL protein (VHLs) is evolutionarily conserved. Herein we present evidence that VHLs associates with ribosome complex via interaction with the large subunit 6 (RPL6). Manipulation of VHLs expression significantly alters protein synthesis, cell size and mitochondrial mass. VHLs deficiency leads to remarkable sensitivity to drug treatments eliciting nascent protein mis-folding and translational errors. The ubiquitination of nascent peptides are dramatically increased upon the ectopic over-expression of VHLs, which simultaneously co-localizes with proteasome and thus may facilitate the ubiquitin-proteasome mediated degradation. In summary, VHLs contributes to protein quality control in addition to its canonical function in maintaining homeostasis of hypoxia-induced factors alpha subunit (HIFα) in response to environmental oxygen supply.