scholarly journals SUMOylation of the small GTPase ARL-13 promotes ciliary targeting of sensory receptors

2012 ◽  
Vol 199 (4) ◽  
pp. 589-598 ◽  
Author(s):  
Yujie Li ◽  
Qing Zhang ◽  
Qing Wei ◽  
Yuxia Zhang ◽  
Kun Ling ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Autosomal Dominant ◽  
Joubert Syndrome ◽  
Small Gtpase ◽  
Sensory Receptors ◽  
Polycystic Kidney ◽  
C Terminus ◽  
Autosomal Dominant Polycystic Kidney ◽  
Established Role ◽  
Sensory Functions

Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13–null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.

scholarly journals Pkd1 mutation has no apparent effects on peroxisome structure or lipid metabolism

2021 ◽  
Author(s):  
Takeshi Terabayashi ◽  
Luis F Menezes ◽  
Fang Zhou ◽  
Hongyi Cai ◽  
Peter J Walter ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Autosomal Dominant ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Peroxisome Biogenesis ◽  
Polycystic Kidney ◽  
Imaging Studies ◽  
C Terminus ◽  
Autosomal Dominant Polycystic Kidney ◽  
Mutant Cells

AbstractBackgroundMultiple studies of tissue and cell samples from patients and pre-clinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease.MethodsUsing control and Pkd1-/- kidney epithelial cells, we investigated peroxisome abundance, biogenesis and morphology by immunoblotting, immunofluorescent and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl; Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C-terminus or full-length polycystin-1 co-localize with peroxisome markers by imaging studies.ResultsPeroxisome abundance, morphology and peroxisome-related protein expression in Pkd1-/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/- cells, and there was no obvious accumulation of very long chain fatty acids in kidneys of mutant mice. Re-analysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, while providing further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full length polycystin-1 or its C-terminus, a fragment previously shown to go to the mitochondria, showed minimal co-localization with peroxisome markers.ConclusionsOur studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.Key points-While mitochondrial abnormalities and fatty acid oxidation impairment have been reported in ADPKD, no studies have investigated if peroxisome dysfunction contributes to these defects.-We investigated peroxisome morphology, biogenesis and function in cell and animal models of ADPKD and investigated whether polycystin-1 co-localized with peroxisome proteins.-Our studies show that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.

scholarly journals Molecular Pathways and Therapies in Autosomal-Dominant Polycystic Kidney Disease

Physiology ◽  
2015 ◽  
Vol 30 (3) ◽  
pp. 195-207 ◽  
Author(s):  
Takamitsu Saigusa ◽  
P. Darwin Bell
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Molecular Pathways ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Multiple Cysts ◽  
Review Current

Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can eventually lead to kidney failure. Studies investigating the role of primary cilia and polycystins have significantly advanced our understanding of the pathogenesis of PKD. This review will present clinical and basic aspects of ADPKD, review current concepts of PKD pathogenesis, evaluate potential therapeutic targets, and highlight challenges for future clinical studies.

scholarly journals Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease

2020 ◽  
Vol 31 (5) ◽  
pp. 1035-1049 ◽  
Author(s):  
Amandine Viau ◽  
Maroua Baaziz ◽  
Amandine Aka ◽  
Manal Mazloum ◽  
Clément Nguyen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Polycystic Kidneys ◽  
Renal Inflammation ◽  
Tubular Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

BackgroundThe inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression.MethodTo explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1, Stat3, and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines.ResultsOur findings indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1-deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells.ConclusionsSTAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

scholarly journals Cellular Activation Triggered by the Autosomal Dominant Polycystic Kidney Disease Gene Product PKD2

1999 ◽  
Vol 19 (5) ◽  
pp. 3423-3434 ◽  
Author(s):  
Thierry Arnould ◽  
Lorenz Sellin ◽  
Thomas Benzing ◽  
Leonidas Tsiokas ◽  
Herbert T. Cohen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Germ Line ◽  
Signaling Cascades ◽  
Polycystic Kidney ◽  
Functional Connection ◽  
C Terminus ◽  
Mitogen Activated Protein ◽  
Autosomal Dominant Polycystic Kidney

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) ɛ, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC α and PKC ɛ, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.

More than colocalizing with polycystin-1, polycystin-l is in the centrosome

2006 ◽  
Vol 291 (2) ◽  
pp. F395-F406 ◽  
Author(s):  
Eva-Flore Bui-Xuan ◽  
Qiang Li ◽  
Xing-Zhen Chen ◽  
Catherine A. Boucher ◽  
Richard Sandford ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Subcellular Fractionation ◽  
Cell Contact ◽  
Polycystic Kidney ◽  
Common Distribution ◽  
Confluent Cell ◽  
Autosomal Dominant Polycystic Kidney ◽  
Renal Cell Lines

Polycystin-1 and polycystin-2 are involved in autosomal dominant polycystic kidney disease by unknown mechanisms. These two proteins are located in primary cilia where they mediate mechanosensation, suggesting a link between cilia function and renal disease. In this study, we sought to characterize the subcellular localization of polycystin-l, a closely related member of polycystin-2, in epithelial renal cell lines. We have shown that endogenous polycystin-l subcellular distribution is different in proliferative and nonproliferative cultures. Polycystin-l is found mostly in the endoplasmic reticulum in subconfluent cell cultures, while in confluent cells it is redistributed to sites of cell-cell contact and to the primary cilium as is polycystin-1. Subcellular fractionation confirmed a common distribution of polycystin-l and polycystin-1 in the fractions corresponding to those containing the plasma membrane of postconfluent cells. Reciprocal coimmunoprecipitation experiments showed that polycystin-l was associated with polycystin-1 in a common complex in both subconfluent and confluent cell cultures. Interestingly, we also identified a novel site for a polycystin member (polycystin-l) in unciliated cells, the centrosome, which allowed us to reveal an involvement of polycystin-l in cell proliferation.

scholarly journals Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

2019 ◽  
Author(s):  
Amandine Viau ◽  
Maroua Baziz ◽  
Amandine Aka ◽  
Clément Nguyen ◽  
E. Wolfgang Kuehn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Polycystic Kidneys ◽  
Renal Inflammation ◽  
Tubular Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

ABSTRACTThe inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes STAT3 activation. Surprisingly, while disrupting Stat3 in Pkd1 deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

scholarly journals Loss of polycystins suppresses deciliation via the activation of the centrosomal integrity pathway

2020 ◽  
Vol 3 (9) ◽  
pp. e202000750 ◽  
Author(s):  
Vasileios Gerakopoulos ◽  
Peter Ngo ◽  
Leonidas Tsiokas
Keyword(s):  
Cell Cycle ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Cyclic Pattern ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cystic Growth

The primary cilium is a microtubule-based, antenna-like organelle housing several signaling pathways. It follows a cyclic pattern of assembly and deciliation (disassembly and/or shedding), as cells exit and re-enter the cell cycle, respectively. In general, primary cilia loss leads to kidney cystogenesis. However, in animal models of autosomal dominant polycystic kidney disease, a major disease caused by mutations in the polycystin genes (Pkd1 or Pkd2), primary cilia ablation or acceleration of deciliation suppresses cystic growth, whereas deceleration of deciliation enhances cystogenesis. Here, we show that deciliation is delayed in the cystic epithelium of a mouse model of postnatal deletion of Pkd1 and in Pkd1- or Pkd2-null cells in culture. Mechanistic experiments show that PKD1 depletion activates the centrosomal integrity/mitotic surveillance pathway involving 53BP1, USP28, and p53 leading to a delay in deciliation. Reduced deciliation rate causes prolonged activation of cilia-based signaling pathways that could promote cystic growth. Our study links polycystins to cilia dynamics, identifies cellular deciliation downstream of the centrosomal integrity pathway, and helps explain pro-cystic effects of primary cilia in autosomal dominant polycystic kidney disease.

scholarly journals Pkd1 mutation has no apparent effects on peroxisome structure or lipid metabolism

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0000962021
Author(s):  
Takeshi Terabayashi ◽  
Luis F. Menezes ◽  
Fang Zhou ◽  
Hongyi Cai ◽  
Peter J. Walter ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Kidney Disease ◽  
Autosomal Dominant ◽  
Peroxisome Biogenesis ◽  
Polycystic Kidney ◽  
Imaging Studies ◽  
C Terminus ◽  
Autosomal Dominant Polycystic Kidney ◽  
Mutant Cells

Background: Multiple studies of tissue and cell samples from patients and pre-clinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. Methods: Using control and Pkd1-/-kidney epithelial cells, we investigated peroxisome abundance, biogenesis and morphology by immunoblotting, immunofluorescent and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl; Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C-terminus or full-length polycystin-1 co-localize with peroxisome markers by imaging studies. Results: Peroxisome abundance, morphology and peroxisome-related protein expression in Pkd1 -/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/-cells, and there was no obvious accumulation of very long chain fatty acids in kidneys of mutant mice. Re-analysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, while providing further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full length polycystin-1 or its C-terminus, a fragment previously shown to go to the mitochondria, showed minimal co-localization with peroxisome markers restricted to putative mitochondrion-peroxisome contact sites. Conclusions: Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid (FA) metabolism.

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