Kurz research group uncovers the molecular mechanism underlying some forms of hypertension
Hypertension is a major public health problem with an estimated 30% of the adult population in the UK suffering from the disease. If left untreated, hypertension turns into a 'silent killer', as it strongly increases an individual's risk of heart disease or stroke.
Some forms of hypertension are hereditary and in recent years it was uncovered that mutations in enzymes of the ubiquitin-proteasome system cause a sub-type familial hypertension called Pseudohypoaldosteronism type II (PHAII). Defects in an E3 ubiquitin ligase complex consisting of the Cullin CUL3 and the substrate adaptor KLHL3 lead to a misregulation of a signaling pathway in the kidney that causes excessive retention of salt, which results in an increase in circulating blood volume and consequently high blood pressure.
Earlier work by the Kurz laboratory had established that the critical substrates of this ligase in regulating salt uptake are kinases of the WNK family. These enzymes are normally ubiquitylated by CUL3/KLHL3, which leads to their degradation by the proteasome. This regulation is critical to maintain salt homeostasis. Hypertension-causing mutations in KLHL3, the substrate adaptor of the complex, were previously shown by the Kurz group to lose binding to WNKs, leading to their ectopic stabilization. Some patients, however, carry mutations in CUL3 and the molecular mechanism of how these mutations lead to hypertension was unresolved.
Work by Frances-Rose Schumacher, a postdoc in the group of Thimo Kurz, now uncovered the molecular defects caused by these patient mutations. The mutations in CUL3 lead to increased structural flexibility that prevents the E3 ligase from directing ubiquitin towards its bound WNK substrates. Ubiquitin is instead erroneously linked to CUL3, causing its ectopic degradation. CUL3 furthermore loses interaction with important functional regulators, the COP9 Signalosome and CAND1.
Frances' work further showed that mice carrying the human CUL3 mutations develop hypertension through the stabilization of WNK kinases, but the analysis of the mouse phenotype also revealed that there is likely an additional vascular contribution to hypertension. This novel finding may explain why patients with CUL3 mutation develop a more severe form of hypertension than patients carrying KLHL3 mutations.
This work was executed in a very fruitful collaboration with Keith Siew and Kevin O'Shaughnessy at the University of Cambridge and is reported in the most recent issue of EMBO Molecular Medicine.
Some forms of hypertension are hereditary and in recent years it was uncovered that mutations in enzymes of the ubiquitin-proteasome system cause a sub-type familial hypertension called Pseudohypoaldosteronism type II (PHAII). Defects in an E3 ubiquitin ligase complex consisting of the Cullin CUL3 and the substrate adaptor KLHL3 lead to a misregulation of a signaling pathway in the kidney that causes excessive retention of salt, which results in an increase in circulating blood volume and consequently high blood pressure.
Earlier work by the Kurz laboratory had established that the critical substrates of this ligase in regulating salt uptake are kinases of the WNK family. These enzymes are normally ubiquitylated by CUL3/KLHL3, which leads to their degradation by the proteasome. This regulation is critical to maintain salt homeostasis. Hypertension-causing mutations in KLHL3, the substrate adaptor of the complex, were previously shown by the Kurz group to lose binding to WNKs, leading to their ectopic stabilization. Some patients, however, carry mutations in CUL3 and the molecular mechanism of how these mutations lead to hypertension was unresolved.
Work by Frances-Rose Schumacher, a postdoc in the group of Thimo Kurz, now uncovered the molecular defects caused by these patient mutations. The mutations in CUL3 lead to increased structural flexibility that prevents the E3 ligase from directing ubiquitin towards its bound WNK substrates. Ubiquitin is instead erroneously linked to CUL3, causing its ectopic degradation. CUL3 furthermore loses interaction with important functional regulators, the COP9 Signalosome and CAND1.
Frances' work further showed that mice carrying the human CUL3 mutations develop hypertension through the stabilization of WNK kinases, but the analysis of the mouse phenotype also revealed that there is likely an additional vascular contribution to hypertension. This novel finding may explain why patients with CUL3 mutation develop a more severe form of hypertension than patients carrying KLHL3 mutations.
This work was executed in a very fruitful collaboration with Keith Siew and Kevin O'Shaughnessy at the University of Cambridge and is reported in the most recent issue of EMBO Molecular Medicine.