Von Hippel-Lindau (VHL) prevents excessive protein aggregation and mediates aggrephagy by modulating the liquidity of p62 condensates

Loss of proteostasis can cause protein aggregation and trigger aggrephagy, yet how these biological processes are coordinated remains unclear. Here, we showed that p62 condensates transit from a gel-like to a more liquid-like state in response to proteotoxic stress. VHL was recruited to aggresomes and colocalizes with p62, which is crucial for p62 to perform its distinct functions in aggresome formation and autophagic degradation. Mechanistically, VHL binds to p62 through its IDR1 region and increases the liquid-like properties via IDR2 region. VHL depletion or disease-associated IDR2 mutations impair p62 condensate dynamics, leading to excessive accumulation of aggregated proteins and concomitant KEAP1 sequestration/NRF2 stabilization. A chimeric peptide linking the p62 PB1 domain to VHL IDR2 recapitulates VHL’s fluidity-promoting activity and suppresses tumorigenesis and protein aggregation. Overall, our findings reveal an HIF-independent tumor-suppressive role of VHL in regulating proteostasis and suggest a new treatment for cancer through the targeting of condensate dynamics. VHL shows an unexpected HIF-independent role in maintaining protein homeostasis under proteotoxic stress, namely, by increasing the liquidity of p62 condensates and orchestrating aggresome formation and subsequent aggrephagy.