The CUL3–KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction

Ohta, Akihito; Schumacher, Frances-Rose; Mehellou, Youcef; Johnson, Clare; Knebel, Axel; Macartney, Thomas; Wood, Nicola T.; Alessi, Dario R.; Kurz, Thimo

doi:10.1042/bj20121903

Cited by 190 publications

(237 citation statements)

References 38 publications

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“…Interestingly, S433 is recurrently mutated in autosomal dominant PHAII (4,26). Mutation of S433 abrogates WNK4 binding and degradation, increasing WNK4 levels (22,23). This observation suggested that S433 phosphorylation might modulate KLHL3 binding and degradation of WNK4.…”

Section: Resultsmentioning

confidence: 95%

“…[16][17][18][19][20][21], and WNK4 function can be modulated by phosphorylation (21). CUL3/KLHL3 has been shown to target WNK4 and WNK1 for ubiquitination and degradation, and disease-causing mutations impair this binding and degradation (22)(23)(24). In particular, dominant mutations in the Kelch domain of KLHL3 prevent binding to WNKs; reciprocally, disease-causing point mutations in WNK4 also prevent WNK4-KLHL3 binding.…”

Section: Significancementioning

confidence: 99%

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Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Shibata

Arroyo

Castañeda‐Bueno

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K + reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K + secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)-components of an E3 ubiquitin ligase complex that targets WNKs for degradation-cause constitutively increased renal salt reabsorption and impaired K + secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3 S433 phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K + secretion in the setting of volume depletion.renin-angiotensin-aldosterone system | distal tubule | hypertension | posttranslational modification | PHAII H ypertension affects 1 billion people worldwide and is a major risk factor for death from stroke, myocardial infarction, and congestive heart failure. The study of Mendelian forms of hypertension has demonstrated the key role of increased renal salt reabsorption in disease pathogenesis (1-4). Observational and intervention trials (5, 6) also indicate that increased dietary K + lowers blood pressure; however, the mechanism of this effect has been unclear.Pseudohypoaldosteronism type II (PHAII; Online Mendelian Inheritance in Man no. 145260), featuring hypertension and hyperkalemia, has revealed a previously unrecognized mechanism that regulates the balance between renal salt reabsorption and K + secretion in response to aldosterone (7). Aldosterone is produced by the adrenal glomerulosa in volume depletion, in response to angiotensin II (AII), and in hyperkalemia via membrane depolarization (8). In volume depletion, aldosterone maximizes renal salt reabsorption, whereas in hyperkalemia, aldosterone promotes maximal renal K + secretion. Volume depletion increases both the NaCl cotransporter (NCC) (9) and electrogenic Na + reabsorption via the epithelial Na + channel (ENaC) (10). The lumen-negative potential produced by ENa...

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Section: Resultsmentioning

confidence: 95%

Section: Significancementioning

confidence: 99%

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Shibata

Arroyo

Castañeda‐Bueno

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Interestingly, KLHL2 protein was also increased by Cul3 knockdown, suggesting that KLHL2 protein may be regulated by Cul3-based E3 ligase as shown for KLHL3. 5 However, such an increase of KLHL2 did not lead to a reduction in WNK3 protein under the Cul3 knockdown condition, clearly suggesting that Cul3 is necessary for KLHL2-mediated WNK3 degradation. AngII could still decrease KLHL2 under the Cul3 knockdown condition (Figure 7), suggesting that the increased degradation of KLHL2 by AngII may be independent of Cul3.…”

Section: Klhl2 Regulates Wnk3 Protein Levels In Movas Cellsmentioning

confidence: 96%

“…Each of them forms a complex with Cul3 and acts as E3 ligase on WNK1/WNK2/WNK3/ WNK4. [4][5][6]19,20 The KLHL3-Cul3 complex acts as an E3 ubiquitin ligase for WNK kinases, and KLHL3 mutations have been reported to cause PHAII through the impaired ubiquitination of WNK4. 4 However, the involvement of WNK kinase regulation by ubiquitination in the situation other than PHAII has not been identified.…”

Section: Discussionmentioning

confidence: 99%

Kelch-Like Protein 2 Mediates Angiotensin II–With No Lysine 3 Signaling in the Regulation of Vascular Tonus

Zeniya

Morimoto

Takahashi

et al. 2015

Journal of the American Society of Nephrology

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Recently, the kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3-STE20/SPS1-related proline/alanine-rich kinase-Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII). In this study, we investigated the involvement of KLHL proteins in AngII-induced WNK3 activation of vascular smooth muscle cells. In the mouse aorta and mouse vascular smooth muscle (MOVAS) cells, KLHL3 was not expressed, but KLHL2, the closest homolog of KLHL3, was expressed. Salt depletion and acute infusion of AngII decreased KLHL2 and increased WNK3 levels in the mouse aorta. Notably, the AngII-induced changes in KLHL2 and WNK3 expression occurred within minutes in MOVAS cells. Results of KLHL2 overexpression and knockdown experiments in MOVAS cells confirmed that KLHL2 is the major regulator of WNK3 protein abundance. The AngII-induced decrease in KLHL2 was not caused by decreased transcription but increased autophagy-mediated degradation. Furthermore, knockdown of sequestosome 1/p62 prevented the decrease in KLHL2, suggesting that the mechanism of KLHL2 autophagy could be selective autophagy mediated by sequestosome 1/p62. Thus, we identified a novel component of signal transduction in AngII-induced vascular contraction that could be a promising drug target. 26: 212926: -213826: , 201526: . doi: 10.1681 Recently, the kelch-like protein 3 (KLHL3) and Cullin3 (Cul3) were identified as the genes responsible for a hereditary hypertensive diseasepseudohypoaldosteronism type II (PHAII). 1 Because the with no lysine (WNK) kinases (WNK1 and WNK4) had already been identified as the responsible genes for PHAII and the KLHL proteins were known to serve as substrate adaptors of Cul3-based E3 ubiquitin ligase, 1-3 we speculated and recently showed that KLHL3 functions as an E3 ligase with Cul3 for WNK4 and that the impaired ubiquitination of WNK4 and its subsequent increase within the cell stimulates the downstream OSR1/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter signaling and causes PHAII. 4 In addition to WNK4, WNK1 and other WNK kinases (WNK2 and WNK3) have been identified as substrates of KLHL3-Cul3 E3 ligase, because KLHL3 can bind to all WNKs in a highly conserved domain (acidic domain). 5 Furthermore, we recently reported that KLHL2 possesses a kelch repeat domain (WNK binding domain) highly similar to that of KLHL3 and that J Am Soc Nephrol

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“…Although mutations in Kelchlike 3 and Cullin-3 cause hyperkalemic hypertension that is reversible with thiazides, these proteins probably do not interact directly with NCC. Instead, Kelch-like 3 binds and ubiquitinates WNK4 and the subsequent degradation of WNK4 would be expected to increase NCC activity (Figure 3) [89,106,128,132].…”

Section: Ubiquitin Ligasesmentioning

confidence: 99%

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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The CUL3–KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction

Cited by 190 publications

References 38 publications

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Kelch-Like Protein 2 Mediates Angiotensin II–With No Lysine 3 Signaling in the Regulation of Vascular Tonus

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

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