The emerging role of sorting nexins in cardiovascular diseases

Yang, Jian; Villar, Van Anthony M.; Rozyyev, Selim; José, Pedro A.; Zeng, Chunyu

doi:10.1042/cs20190034

Cited by 48 publications

(52 citation statements)

References 105 publications

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“…The sorting nexin 1 (SNX) family is comprised of a diverse group of cytoplasmic‐ and membrane‐associated proteins that are involved in various aspects of receptor endocytosis and trafficking through the endosomes 10 . SNX1 homodimerizes or heterodimerizes with SNX2 to form the membrane‐targeting subunit of the mammalian retromer.…”

Section: Introductionmentioning

confidence: 99%

Sorting nexin 1 loss results in increased oxidative stress and hypertension

et al. 2020

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Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1−/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1R), NADPH oxidase (NOX) subunits, D5R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1‐/‐ mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro‐American males had deficient SNX1 activity, impaired D5R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro‐American males. siRNA‐mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5R agonist‐induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over‐expression of SNX1. Among HT African‐Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

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Section: Introductionmentioning

confidence: 99%

Sorting nexin 1 loss results in increased oxidative stress and hypertension

et al. 2020

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“…Sorting nexins are implemented in the development of cardiovascular diseases such as hypertension, coronary heart disease, and heart failure [19]. Here SNXs influence the maintenance of blood pressure by regulating the expression and function of GPCRs such as dopamine receptors, ion channels, and transporters [19,117,177].Consistent with this, knockdown/knockout animal models of SNX1, SNX5, and SNX19 correlate with hypertension. This has led testing if SNXs could potentially be a therapeutic target for hypertension.…”

Section: The Role Of Sorting Nexins In Cardiovascular Diseasementioning

confidence: 87%

“…This has led testing if SNXs could potentially be a therapeutic target for hypertension. Therapeutic strategies have focused on expressing specific SNX subtypes within the kidney to decrease blood pressure [19].…”

Section: The Role Of Sorting Nexins In Cardiovascular Diseasementioning

confidence: 99%

“…Underlying their importance, genetic defects in SNX proteins have been linked with a variety of human diseases including neurodegenerative, cardiovascular diseases, and cancer [18,19]. In this review, we will discuss the growing evidence of SNXs in these three protein quality control pathways and as well as the interplay between SNXs and ubiquitin.…”

Section: Introductionmentioning

confidence: 99%

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Sorting Nexins in Protein Homeostasis

Hanley¹,

Cooper²

2020

Preprint

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Sorting nexins (SNXs) are a highly conserved membrane-associated protein family that plays a role in regulating protein homeostasis. This family of proteins is unified by their characteristic phox (PX) phosphoinositides binding domain. Along with binding to membranes, this family of SNXs also comprises a diverse array of protein-protein interaction motifs that are required for cellular sorting and protein trafficking. SNXs play a role in maintaining the integrity of the proteome which is essential for regulating multiple fundamental processes such as cell cycle progression, transcription, metabolism, and stress response. To tightly regulate these processes proteins must be expressed and degraded in the correct location and at the correct time. The cell employs several proteolysis mechanisms to ensure that proteins are selectively degraded at the appropriate spatiotemporal conditions. SNXs play a role in ubiquitin-mediated protein homeostasis at multiple levels including cargo localization, recycling, degradation, and function. In this review, we will discuss the role of SNXs in three different protein homeostasis systems: endocytosis lysosomal, the ubiquitin-proteasomal, and the autophagy-lysosomal system. The highly conserved nature of this protein family by beginning with the early research on SNXs and protein trafficking in yeast and lead into their important roles in mammalian systems. Underlying the importance of SNXs in protein homeostasis, genetic defects in SNXs have been linked with a variety of human diseases such as cancer, cardiovascular disease, neurogenerative disease, and viral infections.

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“…SNX-BAR proteins are involved in several cellular processes that depend upon membrane remodeling, including protein and lipid trafficking to and from the endosome, endocytosis, and autophagy [5][6][7] . Defects in SNX-BAR function are associated with tumorigenesis, neurodegenerative diseases, and cardiovascular defects 8,9 .…”

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confidence: 99%

The cryo-EM structure of the SNX–BAR Mvp1 tetramer

et al. 2020

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Sorting nexins (SNX) are a family of PX domain-containing proteins with pivotal roles in trafficking and signaling. SNX-BARs, which also have a curvature-generating Bin/Amphiphysin/Rvs (BAR) domain, have membrane-remodeling functions, particularly at the endosome. The minimal PX-BAR module is a dimer mediated by BAR-BAR interactions. Many SNX-BAR proteins, however, additionally have low-complexity N-terminal regions of unknown function. Here, we present the cryo-EM structure of the full-length SNX-BAR Mvp1, which is an autoinhibited tetramer. The tetramer is a dimer of dimers, wherein the membrane-interacting BAR surfaces are sequestered and the PX lipid-binding sites are occluded. The N-terminal low-complexity region of Mvp1 is essential for tetramerization. Mvp1 lacking its N-terminus is dimeric and exhibits enhanced membrane association. Membrane binding and remodeling by Mvp1 therefore requires unmasking of the PX and BAR domain lipid-interacting surfaces. This work reveals a tetrameric configuration of a SNX-BAR protein that provides critical insight into SNX-BAR function and regulation.

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The emerging role of sorting nexins in cardiovascular diseases

Cited by 48 publications

References 105 publications

Sorting nexin 1 loss results in increased oxidative stress and hypertension

Sorting nexin 1 loss results in increased oxidative stress and hypertension

Sorting Nexins in Protein Homeostasis

The cryo-EM structure of the SNX–BAR Mvp1 tetramer

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