Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo

Yoshida, Sayaka; Araki, Younosuke; Mori, Takayasu; Sasaki, Emi; Kasagi, Y; Isobe, Kiyoshi; Susa, Koichiro; Inoue, Yuichi; Bomont, Pascale; Okado, Tomokazu; Rai, Tatemitsu; Uchida, Shinichi; Sohara, Eisei

doi:10.1007/s10157-018-1593-z

Cited by 22 publications

(36 citation statements)

References 35 publications

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“…53 Furthermore, CUL3D9 showed a similar effect on the substrate adaptors, both in vitro 36,37 and in vivo. 42 Because CUL3D9 also has an impaired interaction with the CSN, the results are consistent with decreased CSN activity as a partial mechanism for the disease. Additionally, the selectiveness of CSN inactivation to decrease KLHL3 but not Keap1 abundance may explain why the disease phenotype is only observed in the kidney and smooth muscle.…”

Section: Discussionsupporting

confidence: 58%

“…37 Although this hypothesis has proved controversial, 11 genetic deletion of KLHL3 does lead to a mouse phenotype that resembles FHHt, 41 and recent results confirm that low KLHL3 abundance in mice carrying the pathogenic CUL3D9 mutation contributes to the phenotype. 42 Here, we tested the hypothesis that defective CSN action contributes to the FHHt phenotype mice by deleting a component of the key enzyme involved in removing NEDD8 from the cullin proteins. The results confirm a role for deficient deneddylation for the disease process, but also provide novel insight into factors regulating NCC abundance, in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway

Cornelius

Cuevas

et al. 2018

JASN

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Background The familial hyperkalemic hypertension (FHHt) cullin 3 (CUL3) mutant does not degrade WNK kinases normally, thereby leading to thiazide-sensitive Na-Cl cotransporter (NCC) activation. CUL3 mutant (CUL3D9) does not bind normally to the COP9 signalosome (CSN), a deneddylase involved in regulating cullin-RING ligases. CUL3D9 also caused increased degradation of the CUL3-WNK substrate adaptor kelch-like 3 (KLHL3). Here, we sought to determine how defective CSN action contributes to the CUL3D9 phenotype.Methods The Pax8/LC1 mouse system was used to generate mice in which the catalytically active CSN subunit, Jab1, was deleted only along the nephron, after full development (KS-Jab1 2/2 ).Results Western blot analysis demonstrated that Jab1 deletion increased the abundance of neddylated CUL3. Moreover, total CUL3 expression was reduced, suggesting decreased CUL3 stability. KLHL3 was almost completely absent in KS-Jab1 2/2 mice. Conversely, the protein abundances of WNK1, WNK4, and SPAK kinases were substantially higher. Activation of WNK4, SPAK, and OSR1 was indicated by higher phosphorylated protein levels and translocation of the proteins into puncta, as observed by immunofluorescence. The ratio of phosphorylated NCC to total NCC was also higher. Surprisingly, NCC protein abundance was low, likely contributing to hypokalemia and Na + and K + wasting. Additionally, long-term Jab1 deletion resulted in kidney damage.Conclusions Together, the results indicate that deficient CSN binding contributes importantly to the FHHt phenotype. Although defective CUL3D9-faciliated WNK4 degradation likely contributes, dominant effects on KLHL3 may be a second factor that is necessary for the phenotype.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway

Cornelius

Cuevas

et al. 2018

JASN

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“…KLHL3 destruction was prevented by the neddylation inhibitor MLN4924, sug-gesting that the altered function of CUL3⌬9 was from hyperneddylation. These findings were confirmed by us and others (10,13,28,39) and suggested that KLHL3 degradation contributes to WNK4 accumulation. Schumacher et al (28) further demonstrated impaired CSN activity toward CUL3⌬9 by showing that the mutation had a decreased rate of deneddylation.…”

Section: Csn Binding and Activity Toward Cul3⌬9 Is Disruptedsupporting

confidence: 82%

Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding

Cornelius

Yang

Ellison

2020

American Journal of Physiology-Renal Physiology

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The discovery of new genetic mutations that cause hypertension has illuminated previously unrecognized physiological pathways. One such regulatory pathway was identified when mutations in with no lysine kinase (WNK)4, Kelch-like 3 ( KLHL3), and cullin 3 ( CUL3) were shown to cause the disease familial hyperkalemic hypertension (FHHt). Mutations in all three genes upregulate the NaCl cotransporter (NCC) due to an impaired ability to degrade WNK protein through the cullin-RING-ligase (CRL) ubiquitin-proteasome system. The CUL3 FHHt mutations cause the most severe phenotype, yet the precise mechanism by which these mutations cause the disease has not been established and current proposed models are controversial. New data have identified a possible novel mechanism involving dysregulation of CUL3 activity by the COP9 signalosome (CSN). The CSN interaction with mutant CUL3 is diminished, causing hyperneddylation of the CRL. Recent work has shown that direct renal CSN impairment mimics some aspects of the CUL3 mutation, including lower KLHL3 abundance and activation of the WNK-NCC pathway. Furthermore, in vitro and in vivo studies of CSN inhibition have shown selective degradation of CRL substrate adaptors via auto-ubiquitination, allowing substrate accumulation. In this review, we will focus on recent research that highlights the role of the CSN role in CUL3 mutations that cause FHHt. We will also highlight how these results inform other recent studies of CSN dysfunction.

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“…Meanwhile, kelch-like3 (KLHL3) promotes substrate ubiquitination of bound proteins via interactions of the BTB domain with the cullin 3 component of a cullin-RING E3 ubiquitin ligase complex [43]. Yoshida et al [44] further demonstrated that mice which present a pseudohypoaldosteronism type II (PHA II) phenotype (i.e., a hereditary hypertensive disease) exhibit a significant decrease in KLHL3 expression in both kidney and brain tissues, thereby indicating that KLHL3 may contribute to hereditary hypertension. Since hypertension is an important risk factor for aneurysm rupture, abnormal expression of KLHL3 may be associated with the onset and rupture of IAs.…”

Section: Categorymentioning

confidence: 99%

Weighted gene co-expression network analysis identified six hub genes associated with rupture of intracranial aneurysms

et al. 2020

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Intracranial aneurysms (IAs) are characterized by localized dilation or ballooning of a cerebral artery. When IAs rupture, blood leaks into the space around the brain to create a subarachnoid hemorrhage. The latter is associated with a higher risk of disability and mortality. The aims of this study were to gain greater insight into the pathogenesis of ruptured IAs, and to clarify whether identified hub genes represent potential biological markers for assessing the likelihood of IA progression and rupture. Briefly, the GSE36791 and GSE73378 datasets from the National Center of Biotechnology Information Gene Expression Omnibus database were reanalyzed and subjected to a weighted gene co-expression network analysis to test the association between gene sets and clinical features. The clinical significance of these genes as potential biomarkers was also examined, with their expression validated by quantitative real-time PCR. A total of 14 co-expression modules and 238 hub genes were identified. In particular, three modules (labeled turquoise, blue, and brown) were found to highly correlate with IA rupture events. Additionally, six potential biomarkers were identified (BASP1, CEBPB, ECHDC2, GZMK, KLHL3, and SLC2A3), which are strongly associated with the progression and rupture of IAs. Taken together, these findings provide novel insights into potential molecular mechanisms responsible for IAs and they highlight the potential for these particular genes to serve as biomarkers for monitoring IA rupture.

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Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo

Cited by 22 publications

References 35 publications

Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway

Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway

Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding

Weighted gene co-expression network analysis identified six hub genes associated with rupture of intracranial aneurysms

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