Syntaxin 16 Binds to Cystic Fibrosis Transmembrane Conductance Regulator and Regulates Its Membrane Trafficking in Epithelial Cells

Gee, Heon Yung; Tang, Bor Luen; Kim, Kyung Hwan; Lee, Min Goo

doi:10.1074/jbc.m110.162438

Cited by 38 publications

(34 citation statements)

References 38 publications

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“…Experiments were performed as described previously (47). GST-PAK1 and GST-Rhotekin beads were purchased from Cytoskeleton Inc. Anti-SGPL1 (AF5535, R&D Systems), anti-BiP (ab21685), anti-β-actin (ab6276, Abcam), anti-CD31 (MA3100, Thermo), anti-RAC1 (610650), anti-CDC42 (610928), anti-GM130 (610822, BD Transduction Laboratories), anti-Myc (sc-789), anti-RHOA (sc-418), anti-WT1 (sc-7385, Santa Cruz Biotechnology Inc.), anti-GOLGB1(HPA011008), anti-α-smooth muscle actin (A2547), anti-FLAG (F3165, SigmaAldrich), anti-HA (11867423001, Roche), and anti-synaptopodin (20-4694, American Research Products) antibodies were purchased from commercial sources.…”

Section: Methodsmentioning

confidence: 99%

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Lovric¹,

Gonçalves²,

Gee³

et al. 2017

Journal of Clinical Investigation

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174

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Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of diseaseassociated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

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Section: Methodsmentioning

confidence: 99%

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Lovric¹,

Gonçalves²,

Gee³

et al. 2017

Journal of Clinical Investigation

Self Cite

181

174

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“…39 Then 50 mg of cell lysates was loaded into each lane. Anti-EMP2 (Abgent), anti-VEGFA, anti-b-actin (Abcam, Inc.), anti-CAV1, anti-phospho-CAV1, and anti-CASPASE3 (Cell Signaling Technology) were purchased from commercial sources.…”

Section: Immunoblottingmentioning

confidence: 99%

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Wan

Chen

Choi

et al. 2016

Journal of the American Society of Nephrology

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Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease-based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury. Nephrotic syndrome (NS) is a CKD defined by nephrotic-range proteinuria caused by disruption of the renal glomerular filtration barrier, resulting in hypoalbuminemia, hyperlipidemia, and edema. Childhood NS, if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. 1 NS is classified by response or nonresponse to a standardized glucocorticosteroid therapy as steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS), respectively. Recent studies of SRNS have identified monogenic causes of SRNS to reside in podocytespecific genes, which if mutated, lead to podocyte dysfunction and defective glomerular filtration barrier. 2 Using the combined approach of homozygosity mapping and whole-exome sequencing, we have previously identified mutations in epithelial membrane protein 2 (EMP2) as a novel monogenic cause for NS. 3 EMP2 was initially identified by its homology with the growth-arrest-specific 3/peripheral myelin protein 22 family 4 and negatively regulates the mRNA and protein levels of CAV1, a major protein component of plasma membrane microdomain caveolae. 5,6 To explore the pathogenic mechanism underlying EMP2 mutations, we have now generated emp2

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“…The SNARE domain of STXs consists of a highly conserved coiled-coil domain and mediates the trafficking and targeting of intracellular vesicles. STXs also interact with a wide range of plasma membrane proteins and regulate their intracellular trafficking, including sodium channel (15), voltage-gated potassium channel (16), and cystic fibrosis transmembrane conductance regulator (17). However, it has not been known whether STXs regulate the intracellular trafficking of CLDNs.…”

mentioning

confidence: 99%

Tight Junctional Localization of Claudin-16 Is Regulated by Syntaxin 8 in Renal Tubular Epithelial Cells

Ikari

Tonegawa

Sanada

et al. 2014

Journal of Biological Chemistry

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Background: Disease-associated claudin-16 mutants cause mislocalization and decrease reabsorption of Mg 2ϩ in the kidney. Results: Knockdown of syntaxin 8 in kidney cells decreased the tight junctional localization of claudin-16 in parallel with a decrease in Mg 2ϩ permeability. Conclusion: Syntaxin 8 controls the localization of claudin-16. Significance: Our findings provide a new insight into the trafficking mechanism of tight junctional proteins.

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Syntaxin 16 Binds to Cystic Fibrosis Transmembrane Conductance Regulator and Regulates Its Membrane Trafficking in Epithelial Cells

Cited by 38 publications

References 38 publications

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Tight Junctional Localization of Claudin-16 Is Regulated by Syntaxin 8 in Renal Tubular Epithelial Cells

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