Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure
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HYPERTENSION AND THE KIDNEY (RM CAREY, SECTION EDITOR)
Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure Jing Wu 1 & James A. McCormick 2 & Curt D. Sigmund 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review The goal of this review is to evaluate recent advances in understanding the pivotal roles of Cullin-3 (CUL3) in blood pressure regulation with a focus on its actions in the kidney and blood vessels. Recent Findings Cul3-based ubiquitin ligase regulates renal electrolyte transport, vascular tone, and redox homeostasis by facilitating the normal turnover of (1) with-no-lysine kinases in the distal nephron, (2) RhoA and phosphodiesterase 5 in the vascular smooth muscle, and (3) nuclear factor E2-related factor 2 in antioxidant responses. CUL3 mutations identified in familial hyperkalemic hypertension (FHHt) yield a mutant protein lacking exon 9 (CUL3Δ9) which displays dual gain and loss of function. CUL3Δ9 acts in a dominant manner to impair CUL3-mediated substrate ubiquitylation and degradation. The consequent accumulation of substrates and overactivation of downstream signaling cause FHHt through increased sodium reabsorption, enhanced vasoconstriction, and decreased vasodilation. Summary CUL3 ubiquitin ligase maintains normal cardiovascular and renal physiology through posttranslational modification of key substrates which regulate blood pressure. Interference with CUL3 disturbs these key downstream pathways. Further understanding the spatial and temporal specificity of how CUL3 functions in these pathways is necessary to identify novel therapeutic targets for hypertension. Keywords Cullin3 . Ubiquitylation . With-no-lysine kinases . RhoA . Phosphodiesterase 5 . Blood pressure
Introduction Cullin-3 (CUL3) is a scaffold subunit of the CUL3-RING (really interesting new gene)-E3 ubiquitin ligase (CRL3) complex. CUL3 bridges the interaction between the RING protein RBX1 and substrate adaptors which deliver targets for ubiquitylation and proteasomal degradation. This posttranslational modification is an important mechanism that regulates protein turnover and is essential for normal cell biology and organ function. Ubiquitylation and proteasomal degradation are important components in cell cycle [1], circadian rhythm [2], immune cell development [3], vascular tone [4, 5, 6••, This article is part of the Topical Collection on Hypertension and the Kidney * Curt D. Sigmund [email protected] 1
Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509, USA
2
Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, USA
7••], renal sodium transport [8–11], and redox homeostasis [12], among many others. Mounting genetic and physiological evidence supports a critical role of CUL3 in controlling arterial blood pressure (BP). It is no longer controversial that CUL3 mutations cause familial hyperkalemic hypertension (FHHt, a
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