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Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding
- Source :
- Am J Physiol Renal Physiol
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Physiology
COP9 Signalosome Complex
Review
030204 cardiovascular system & hematology
Biology
Cullin Proteins
Distal nephron
Cell biology
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
FAMILIAL HYPERKALEMIC HYPERTENSION
Hypertension
Mutation
biology.protein
Animals
Humans
COP9 signalosome
Regulatory Pathway
Cullin
Signal Transduction
Subjects
Details
- ISSN :
- 15221466
- Volume :
- 318
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Renal physiology
- Accession number :
- edsair.doi.dedup.....b32146fd183d05f8c60608b685dba177