VHL regulates p62 condensate liquidity and protein aggregation

A team from Zhongnan Hospital and the School of Basic Medical Sciences of Wuhan University, with colleagues from Dalian Medical University and the General Hospital of Central Theater Command, has reported how the Von Hippel-Lindau protein (VHL) regulates protein aggregation. The work was published on 4 November 2026 in Nature Communications doi.org. The authors studied how cells coordinate two linked processes: the aggregation of proteins when proteostasis is lost, and aggrephagy, the autophagic removal of those aggregates doi.org.

The authors note that the coordination of these processes has remained unclear. They showed that p62 condensates change from a gel-like to a more liquid-like state in response to proteotoxic stress doi.org.

How VHL changes the state of p62 condensates

According to the authors, VHL is recruited to aggresomes and colocalizes with p62 there doi.org. This is crucial for p62 to perform its distinct functions in aggresome formation and in autophagic degradation doi.org.

Mechanistically, VHL binds to p62 through its IDR1 region. It increases the liquid-like properties of the condensates through its IDR2 region doi.org.

Consequences of VHL loss and the chimeric peptide

VHL depletion, or disease-associated mutations in IDR2, impaired the dynamics of p62 condensates doi.org. This led to excessive accumulation of aggregated proteins. It was accompanied by sequestration of KEAP1 and stabilization of NRF2 doi.org.

The researchers also built a chimeric peptide that links the p62 PB1 domain to VHL IDR2. The peptide recapitulated the fluidity-promoting activity of VHL. The authors report that it suppressed tumorigenesis and protein aggregation doi.org.

The authors conclude that the data point to an HIF-independent tumor-suppressive role of VHL in regulating proteostasis. They suggest that targeting condensate dynamics could serve as a new approach to cancer treatment doi.org. The abstract does not describe clinical testing of the peptide.

Wuhan researchers: VHL keeps p62 condensates liquid, and a chimeric peptide curbs tumorigenesis

How VHL changes the state of p62 condensates

Consequences of VHL loss and the chimeric peptide

Sources · 1

Read also

Argonne demonstrates 4D neutron scattering to track correlated ion motion in a strontium chloride crystal