bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021–05–23
24 papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Therapeutic advances in ADPKD: the future awaits.
  2. Disrupting Polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease.
  3. The TBC1D31/praja2 complex controls primary ciliogenesis through PKA-directed OFD1 ubiquitylation.
  4. The correlation between kidney volume and measured glomerular filtration rate in an Asian ADPKD population: a prospective cohort study.
  5. Radiographic Imaging in Autosomal Dominant Polycystic Kidney Disease: A Claims Analysis.
  6. C3G localizes to mother centriole dependent on cenexin, and regulates centrosome duplication and primary cilia length.
  7. Increasing prevalence of hypertension during long-term follow-up in children with autosomal dominant polycystic kidney disease.
  8. Congenital hepatic fibrosis: case report and review of literature.
  9. PLEKHG4B enables actin cytoskeletal remodeling during epithelial cell-cell junction formation.
  10. Cross Talk Between Renal Transporters and Polycystin-1 as a Potential Molecular Target Involved in Autosomal Dominant Polycystic Kidney Disease.
  11. Fibroblast Growth Factor 23 Is a Valuable Predictor of Autosomal Dominant Polycystic Kidney Disease Progression.
  12. PKD2 deficiency suppresses amino acid biosynthesis in ADPKD by impairing the PERK-TBL2-eIF2ɑ-ATF4 pathway.
  13. Case report: Atypical polycystic kidney disease.
  14. Response to "Fibroblast Growth Factor 23 Is a Valuable Predictor of Autosomal Dominant Polycystic Kidney Disease Progression".
  15. RHOA mediated mechanical force generation through Dectin-1.
  16. Superresolution Microscopy Reveals Distinct Phosphoinositide Subdomains Within the Cilia Transition Zone.
  17. Epb41l5 interacts with IQCB1 and regulates ciliary function in zebrafish embryos.
  18. Artificial Intelligence Approaches to Assessing Primary Cilia.
  19. GDNF drives rapid tubule morphogenesis in novel 3D in vitro model for ADPKD.
  20. RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration.
  21. Emerging role of lncRNAs in the regulation of Rho GTPase pathway.
  22. The IFT20 homolog in Caenorhabditis elegans is required for ciliogenesis and cilia-mediated behavior.
  23. Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome.
  24. Ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling.
  1. J Nephrol. 2021 May 19.
    Therapeutic advances in ADPKD: the future awaits.
    Ivana Capuano, Pasquale Buonanno, Eleonora Riccio, Maria Amicone, Antonio Pisani.
      Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies, representing the fourth cause of end stage renal disease (ESRD), with an estimated prevalence between 1:1000 and 1:2500. It is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy. The advances in the knowledge of multiple molecular pathways involved in the pathophysiology of ADPKD led to the development of several treatments which are currently under investigation. Recently, the widespread approval of tolvaptan and, in Italy, of long-acting release octreotide (octreotide-LAR), represents but the beginning of the new therapeutic management of ADPKD patients. Encouraging results are expected from ongoing randomized controlled trials (RCTs), which are investigating not only drugs acting on the calcium/cyclic adenosin monoposphate (cAMP) pathway, the most studied target so far, but also molecules targeting specific pathophysiological pathways (e.g. epidermal growth factor (EGF) receptor, AMP-activated protein kinase (AMPK) and KEAP1-Nrf2) and sphingolipids. Moreover, studies on animal models and cultured cells have also provided further promising therapeutic strategies based on the role of intracellular calcium, cell cycle regulation, MAPK pathway, epigenetic DNA, interstitial inflammation, and cell therapy. Thus, in a near future, tailored therapy could be the key to changing the natural history of ADPKD thanks to the vigorous efforts that are being made to implement clinical and preclinical studies in this field. Our review aimed to summarize the spectrum of drugs that are available in the clinical practice and the most promising molecules undergoing clinical, animal, and cultured cell studies.
    Keywords:  Autosomal dominant polycystic kidney disease; Glomerular filtration rate; Molecular pathway; Targeted therapy; Total kidney volume
    DOI:  https://doi.org/10.1007/s40620-021-01062-6
  2. J Cell Sci. 2020 Jan 01. pii: jcs.255562. [Epub ahead of print]
    Disrupting Polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease.
    Thuy N Vien, Leo C T Ng, Jessica M Smith, Ke Dong, Matteus Krappitz, Vladimir G Gainullin, Sorin Fedeles, Peter C Harris, Stefan Somlo, Paul G DeCaen.
      Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2. PKD2 encodes polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca2+ modulates polycystin-2 voltage dependent gating and subsequent desensitization- two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca2+ occupancy of the polycytsin-2 intracellular EF hand is responsible for these forms of channel regulation, and if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca2+-EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca2+-EF hand association but do not result in a PKD phenotype. Our findings suggest additional Ca2+ binding sites within polycystin-2 or Ca2+-dependent modifiers are responsible for regulating channel activity.
    Keywords:  ADPKD; Biophysics; Calcium regulation; Ion channels; Polycytsin; Primary cilia
    DOI:  https://doi.org/10.1242/jcs.255562
  3. EMBO J. 2021 May 17. 40(10): e106503
    The TBC1D31/praja2 complex controls primary ciliogenesis through PKA-directed OFD1 ubiquitylation.
    Emanuela Senatore, Francesco Chiuso, Laura Rinaldi, Daniela Intartaglia, Rossella Delle Donne, Emilia Pedone, Bruno Catalanotti, Luciano Pirone, Bianca Fiorillo, Federica Moraca, Giuliana Giamundo, Giovanni Scala, Andrea Raffeiner, Omar Torres-Quesada, Eduard Stefan, Marcel Kwiatkowski, Alienke van Pijkeren, Manuela Morleo, Brunella Franco, Corrado Garbi, Ivan Conte, Antonio Feliciello.
      The primary cilium is a microtubule-based sensory organelle that dynamically links signalling pathways to cell differentiation, growth, and development. Genetic defects of primary cilia are responsible for genetic disorders known as ciliopathies. Orofacial digital type I syndrome (OFDI) is an X-linked congenital ciliopathy caused by mutations in the OFD1 gene and characterized by malformations of the face, oral cavity, digits and, in the majority of cases, polycystic kidney disease. OFD1 plays a key role in cilium biogenesis. However, the impact of signalling pathways and the role of the ubiquitin-proteasome system (UPS) in the control of OFD1 stability remain unknown. Here, we identify a novel complex assembled at centrosomes by TBC1D31, including the E3 ubiquitin ligase praja2, protein kinase A (PKA), and OFD1. We show that TBC1D31 is essential for ciliogenesis. Mechanistically, upon G-protein-coupled receptor (GPCR)-cAMP stimulation, PKA phosphorylates OFD1 at ser735, thus promoting OFD1 proteolysis through the praja2-UPS circuitry. This pathway is essential for ciliogenesis. In addition, a non-phosphorylatable OFD1 mutant dramatically affects cilium morphology and dynamics. Consistent with a role of the TBC1D31/praja2/OFD1 axis in ciliogenesis, alteration of this molecular network impairs ciliogenesis in vivo in Medaka fish, resulting in developmental defects. Our findings reveal a multifunctional transduction unit at the centrosome that links GPCR signalling to ubiquitylation and proteolysis of the ciliopathy protein OFD1, with important implications on cilium biology and development. Derangement of this control mechanism may underpin human genetic disorders.
    Keywords:  OFD1; PKA; praja2; primary cilium; ubiquitin
    DOI:  https://doi.org/10.15252/embj.2020106503
  4. BMC Nephrol. 2021 May 15. 22(1): 178
    The correlation between kidney volume and measured glomerular filtration rate in an Asian ADPKD population: a prospective cohort study.
    Bunyong Phakdeekitcharoen, Watcharapong Treesinchai, Pornphan Wibulpolprasert, Sarinya Boongird, Pinkael Klytrayong.
       BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder that leads to end stage renal disease (ESRD). Cyst expansion in ADPKD is strongly associated with the decline in renal function. However, the correlation between total kidney volume (TKV) and glomerular filtration rate (GFR) at an early stage has not been well demonstrated. There is growing evidence that utilization of estimated GFR (eGFR) may induce misleading information in a population with near normal renal function. Therefore, a more accurate method is essential.
    METHODS: A prospective cohort of ADPKD patients was conducted with clinical data and laboratory collection. Measured GFR (mGFR) was assessed by iohexol plasma clearance method using ultra performance liquid chromatography. eGFR was calculated using the CKD-EPI equation. Kidney volumes were evaluated using MRI imaging protocol.
    RESULTS: Thirty two patients completed the study. The mean age was 56 years old. The mean initial mGFR was 83.8 mL/min/1.73m2. The mean change in mGFR per year was -2.99 mL/min/1.73m2/year. The mean initial height-adjusted TKV (htTKV) was 681.0 mL/m. The mean percentage change in htTKV per year (%ΔhtTKV/y) was 4.77 %/year. mGFR had a better association with clinical parameters than eGFR. Initial mGFR was significantly and inversely correlated with initial htTKV and age. The percentage change in mGFR per year was significantly and inversely correlated with the %ΔhtTKV/y and 24-hr urine albumin. The %ΔhtTKV/y was significantly correlated with initial htTKV.
    CONCLUSIONS: Our studies demonstrated that mGFR using iohexol is a more reliable and accurate method than eGFR for evaluating GFR changes in the early stages of ADPKD patients. There is a strong inverse correlation between kidney volume and mGFR in an Asian ADPKD population. The initial htTKV is a good predictor of kidney volume progression. The %ΔhtTKV/y is a good early surrogate marker for the decline in renal function. 24-hr urine albumin is also a good indicator for renal progression.
    Keywords:  Autosomal dominant polycystic kidney disease (ADPKD); Iohexol; Measured GFR (mGFR); Total kidney volume (TKV); Ultra performance liquid chromatography (UPLC)
    DOI:  https://doi.org/10.1186/s12882-021-02392-0
  5. Int J Nephrol Renovasc Dis. 2021 ;14 133-142
    Radiographic Imaging in Autosomal Dominant Polycystic Kidney Disease: A Claims Analysis.
    Myrlene Sanon Aigbogun, Robert A Stellhorn, Christina S Pao, Stephen L Seliger.
       Background: Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable, with some patients progressing rapidly to end-stage renal disease (ESRD). Abdominal imaging is an important modality for verifying diagnosis in patients at risk for rapidly progressing ADPKD, targeting them for early treatment that could slow onset of ESRD. Published literature is limited on the real-world abdominal imaging utilization patterns in ADPKD.
    Methods: A retrospective healthcare administrative claims analysis examining abdominal imaging scans occurring from January 1, 2014, through June 30, 2017, was conducted using the IBM MarketScan® commercial and Medicare supplemental databases. Patients in the United States who were at least 18 years old and had at least 1 inpatient claim or 2 outpatient claims (with different dates of service) with an ADPKD diagnosis code, as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM codes 753.12 [polycystic kidney, unspecified type] and 753.13 [polycystic kidney, autosomal dominant] and/or Tenth Revision (ICD-10-CM codes Q61.2 [polycystic kidney, adult type] and Q61.3 [polycystic kidney, unspecified]) were included.
    Results: Of the 4637 patients with ADPKD (mean age, 51.2 years [SD = 15.52]), 59% had ≥1 abdominal imaging scan. Of these patients, 46% had ≥1 computed tomography (CT) scan, 25% had ≥1 ultrasound, 10% had ≥1 magnetic resonance imaging scan. Among the 1754 patients (38%) with chronic kidney disease (CKD) stage information, CT imaging was more frequent in later stages (31% stage 1 versus 68% stage 5). The proportion of patients undergoing at least 1 CT or MRI scan increased with disease severity (37% in stage 1, 42% in stage 2, 48% in stage 3, 56% in stage 4, and 71% in stage 5).
    Conclusion: Results of this analysis support the need for further investigation into abdominal imaging utilization in managing patients with ADPKD. Future research could clarify barriers and increase access to imaging, which has the potential to inform risk stratification, help patients delay dialysis or transplantation associated with ESRD, and help health systems avoid the costs associated with ESRD.
    Keywords:  CT scan; MRI; autosomal dominant; cystic; kidney diseases; polycystic kidney; ultrasound
    DOI:  https://doi.org/10.2147/IJNRD.S300331
  6. J Cell Sci. 2020 Jan 01. pii: jcs.243113. [Epub ahead of print]
    C3G localizes to mother centriole dependent on cenexin, and regulates centrosome duplication and primary cilia length.
    Sanjeev Chavan Nayak, Vegesna Radha.
      C3G (RapGEF1) plays a role in cell differentiation and is essential for early embryonic development in mice. In this study, we identify C3G as a centrosomal protein colocalizing with cenexin at the mother centriole in interphase cells. C3G interacts through its catalytic domain with cenexin, and they show interdependence for localization to the centrosome. C3G depletion caused a decrease in cellular cenexin levels. Centrosomal localization is lost as myocytes differentiate to form myotubes. Stable clone of cells depleted of C3G by CRISPR/Cas9 showed the presence of supernumerary centrioles. Overexpression of C3G, or a catalytically active deletion construct inhibited centrosome duplication. Cilia length is longer in C3G knockout cells, and the phenotype could be reverted upon reintroduction of C3G or its catalytic domain. Association of C3G with the basal body is dynamic, decreasing upon serum starvation, and increasing upon reentry into the cell cycle. C3G inhibits cilia formation and length dependent on its catalytic activity. We conclude that C3G inhibits centrosome duplication and maintains ciliary homeostasis, properties that may be important for its role in embryonic development.
    Keywords:  C3G; Cenexin; Centrosome; Mother centriole; Primary cilia; RapGEF1
    DOI:  https://doi.org/10.1242/jcs.243113
  7. Pediatr Nephrol. 2021 May 18.
    Increasing prevalence of hypertension during long-term follow-up in children with autosomal dominant polycystic kidney disease.
    Tomáš Seeman, Petr Jansky, Fencl Filip, Květa Bláhová, Adam Jaroš.
       INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Kidney cysts form over the course of the disease and kidney function slowly declines, usually leading to kidney failure in middle to late adulthood. However, some symptoms, such as hypertension or proteinuria, can be present at an earlier age. In this study, we aimed to quantify early complications in children over time.
    METHODS: All 69 children with ADPKD from our pediatric nephrology center who met inclusion criteria (follow-up ≥ 1 year and ≥ 2 recorded visits) were studied. Analysis of changes in kidney size, cyst count, estimated glomerular filtration rate (eGFR), urinary protein excretion, and blood pressure was performed.
    RESULTS: The median time of follow-up was 6.3 years (range 8.4-14.8). Over the follow-up, kidneys grew from 109 to 115% of expected length (p < 0.0001), number of cysts increased at a rate of 0.8 cyst/kidney/year, and the prevalence of hypertension increased significantly from 20 to 38% (p < 0.015). The eGFR and absolute urinary protein excretion remained stable.
    CONCLUSIONS: This study shows that children with ADPKD suffer from increasing prevalence of hypertension during the course of the disease parallel to the increasing number of kidney cysts and size despite normal and stable kidney function and proteinuria. A higher resolution version of the Graphical abstract is available as Supplementary information.
    Keywords:  Autosomal dominant polycystic kidney disease; Children; Glomerular filtration rate; Hypertension; Proteinuria
    DOI:  https://doi.org/10.1007/s00467-021-05104-w
  8. Pan Afr Med J. 2021 ;38 188
    Congenital hepatic fibrosis: case report and review of literature.
    Brahim El Hasbaoui, Zainab Rifai, Salahiddine Saghir, Anas Ayad, Najat Lamalmi, Rachid Abilkassem, Aomar Agadr.
      Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation; it often coexists with Caroli's disease, von Meyenburg complexes, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). Although CHF was first named and described in detail by Kerr et al. in 1961. Its pathogenesis still remains unclear. The exact incidence and prevalence are not known, and only a few hundred patients with CHF have been reported in the literature to date. However, with the development of noninvasive diagnostic techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), CHF may now be more frequently detected. Anatomopathological examination of liver biopsy is the gold standard in diagnosis of CHF. Patients with CHF exhibit variable clinical presentations, ranging from no symptoms to severe symptoms such as acute hepatic decompensation and even cirrhosis. The most common presentations in these patients are splenomegaly, esophageal varices, and gastrointestinal bleeding due to portal hypertension. In addition, in younger children, CHF often is accompanied by renal cysts or increased renal echogenicity. Great variability exists among the signs and symptoms of the disease from early childhood to the 5th or 6th decade of life, and in most patients the disorder is diagnosed during adolescence or young adulthood. Here, we present two cases of congenital hepatic fibrosis in 2-years-old girl and 12-year-old male who had been referred for evaluation of an abdominal distension with persistent hyper-transaminasemia and cholestasis, the diagnostic was made according to the results of medical imaging (CT or MRI), a liver biopsy, and genetic testing.
    Keywords:  Fibrosis; case report; cholestasis; ciliopathy; hyper-transaminasemia
    DOI:  https://doi.org/10.11604/pamj.2021.38.188.27941
  9. J Cell Sci. 2020 Jan 01. pii: jcs.249078. [Epub ahead of print]
    PLEKHG4B enables actin cytoskeletal remodeling during epithelial cell-cell junction formation.
    Komaki Ninomiya, Kai Ohta, Kazunari Yamashita, Kensaku Mizuno, Kazumasa Ohashi.
      Cell-cell junction formation requires actin cytoskeletal remodeling. Here we show that PLEKHG4B, a Rho-guanine nucleotide exchange factor (Rho-GEF), plays a crucial role in epithelial cell-cell junction formation. Knockdown of PLEKHG4B decreased Cdc42 activity and tended to increase RhoA activity in A549 cells. A549 monolayer cells showed 'closed junctions' with closely packed actin bundles along the cell-cell contacts, but PLEKHG4B knockdown suppressed closed junction formation and exhibited 'open junctions' with split actin bundles located away from the cell-cell boundary. In calcium-switch assays, PLEKHG4B knockdown delayed the conversion of open junctions to closed junctions and β-catenin accumulation at cell-cell junctions. Further, PLEKHG4B knockdown abrogated the reduction in myosin activity normally seen in the later stage of junction formation. The aberrant myosin activation and impairments in closed junction formation in PLEKHG4B-knockdown cells were reverted by ROCK inhibition or LARG/PDZ-RhoGEF knockdown. These results suggest that PLEKHG4B enables actin remodeling during epithelial cell-cell junction maturation, probably by reducing myosin activity in the later stage of junction formation, through suppressing LARG/PDZ-RhoGEF and RhoA-ROCK activities. We also showed that annexin-A2 participates in PLEKHG4B localization to cell-cell junctions.
    Keywords:  Actin organization; Annexin-A2; Cell adhesion; Myosin; PLEKHG4B; Rho-GEF
    DOI:  https://doi.org/10.1242/jcs.249078
  10. Iran J Kidney Dis. 2021 May;15(3): 177-189
    Cross Talk Between Renal Transporters and Polycystin-1 as a Potential Molecular Target Involved in Autosomal Dominant Polycystic Kidney Disease.
    Gobind Ram, Tarini Vats, Anil Kumar, Gulab Singh, Shiv Kumar Giri.
       INTRODUCTION: The mutational changes in Polycystin-1(PC-1) encoded by PKD1 gene is the main cause of Autosomal Dominant Polycystic kidney disease (ADPKD). The pathological changes in renal epithelial cells and multiple cyst formation occur due to activation of cascade of signalling pathways and membrane renal transporters (RTs). Our study have focused on the identification, of different RTs, their interactions with Polycystin-1 and other selected target proteins to find out their role in pathogenesis.
    METHODS: In this study, various RTs protein sequences were identified and retrieved from NCBI's GenBank and UniProt. RTs were categorized according to different nephronal segmenta as per their functional information retrieved from UniProt and Transpoter databases. Further, sequences were subjected for interaction network analysis in String database and Cytoscape 3.7.2. Different interactions including experimentally validated were identified and can be further validated through in vivo methods.
    RESULTS: The cross talk between different RT, Polycystin-1 and other sequences were analysed. The various pathways of the interaction with PC-1 were categorised. The total number of 119 nodes and 769 edges interactions were generated. The results were visualized and cross verified with other databases in cytoscape.
    CONCLUSION: The cross signalling of PKD1 with SCNN1A, SCNN1G, SLC12A1, AVPR2 shows their importance in the cyst formation and in pathogenesis of ADPKD.
  11. Kidney Int Rep. 2021 May;6(5): 1482
    Fibroblast Growth Factor 23 Is a Valuable Predictor of Autosomal Dominant Polycystic Kidney Disease Progression.
    Cheng Xue, Changlin Mei, Jing Xu, Liming Zhang, Zhiguo Mao.
      
    DOI:  https://doi.org/10.1016/j.ekir.2021.03.881
  12. Biochem Biophys Res Commun. 2021 May 17. pii: S0006-291X(21)00782-8. [Epub ahead of print]561 73-79
    PKD2 deficiency suppresses amino acid biosynthesis in ADPKD by impairing the PERK-TBL2-eIF2ɑ-ATF4 pathway.
    Xingquan Zhou, Hui Xiong, Yi Lu, Meijuan Geng, Yumei Lu, Lirong Zhang, Xu Zhu.
      Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism remain elusive. Here we report that amino acid biosynthesis is reprogrammed in Pkd2-knockout mouse kidneys via a defective PERK-eIF2ɑ-ATF4 pathway. Transcriptomic analysis revealed that the amino acid biosynthesis pathways such as serine, arginine and cysteine were impaired, and associated critical enzymes were downregulated in Pkd2-knockout mouse kidneys. ATF4 and CHOP, transcription factors downstream of the endoplasmic reticulum (ER) stress sensor PERK, were identified as master regulators of these enzymes' expression. PKD2 deficiency impaired the expression of ATF4 and amino acid synthesis enzymes in RCTEC cells under ER stress. Mechanistically, as an ER-resident protein, PKD2 interacts with TBL2, which functions as an adaptor bridging eIF2ɑ to PERK. PKD2 depletion impaired the recruitment of eIF2ɑ to TBL2, thus impeding activation of the PERK-eIF2ɑ-ATF4 pathway and downstream amino acid biosynthesis. These findings illuminate a molecular mechanism linking the PKD2-mediated PERK-eIF2ɑ-ATF4 pathway and amino acid metabolic reprogramming in ADPKD.
    Keywords:  ADPKD; ATF4; Amino acid biosynthesis; PKD2; TBL2
    DOI:  https://doi.org/10.1016/j.bbrc.2021.05.012
  13. Radiol Case Rep. 2021 Jul;16(7): 1643-1645
    Case report: Atypical polycystic kidney disease.
    Christopher Shin, Leonard Berliner.
      Atypical or unilateral polycystic kidney disease is a rare entity that is found incidentally and is characterized on imaging as asymmetric or unilateral distribution of cysts confined to the kidneys. We present a case of an incidental finding of atypical polycystic kidney disease in a 72-year-old male. Computed tomography imaging showed asymmetric distribution of cysts only in the kidneys and the patient had no genitourinary symptoms, had normal renal function, and did not have a family history of renal disease. Although considered to be benign, rare cases of progression of atypical polycystic kidney disease to bilateral polycystic kidney disease has been documented in the literature, which portends a worse prognosis. It is important for clinicians to be aware of this entity so that patients can be monitored periodically for progression of disease.
    Keywords:  Atypical polycystic kidney disease; Autosomal dominant polycystic kidney disease; End-Stage Renal Disease; Unilateral renal cystic disease
    DOI:  https://doi.org/10.1016/j.radcr.2021.03.068
  14. Kidney Int Rep. 2021 May;6(5): 1482-1483
    Response to "Fibroblast Growth Factor 23 Is a Valuable Predictor of Autosomal Dominant Polycystic Kidney Disease Progression".
    Alan S L Yu, Mireille El Ters, Jason R Stubbs.
      
    DOI:  https://doi.org/10.1016/j.ekir.2021.03.878
  15. J Cell Sci. 2020 Jan 01. pii: jcs.236166. [Epub ahead of print]
    RHOA mediated mechanical force generation through Dectin-1.
    Rohan P Choraghe, Tomasz Kołodziej, Alan Buser, Zenon Rajfur, Aaron K Neumann.
      Dectin-1 (Dendritic Cell associated C-type Lectin 1) is an innate immune pattern recognition receptor which recognizes β-glucan on the Candida albicans (C. albicans) cell wall. Recognition of β-glucan by immune cells leads to phagocytosis, oxidative burst, cytokine and chemokine production. We looked for specific mechanisms that coordinate phagocytosis downstream of Dectin-1 leading to actin reorganization and internalization of fungus. We found that stimulation of Dectin-1 by soluble β-glucan leads to mechanical force generation and areal contraction in Dectin-1 transfected HEK-293 cells and M1 macrophages. With inhibitor studies, we found this force generation is a SYK (Spleen Tyrosine Kinase)-independent, SFK (SRC Family Kinase)-dependent process mediated through the RHOA (Ras homolog family member type A)-ROCK (Rho associated coiled-coil containing protein kinase)-MLC (Myosin light chain) pathway. We confirmed activation of RHOA downstream of Dectin-1 using activity assays and stress fiber formation. Through phagocytosis assays, we found direct evidence for the importance of RHOA-ROCK-MLC signaling in the process of phagocytosis of C. albicans.
    Keywords:  Candida albicans; Dectin-1; Fungal pathogen; Mechanobiology; RhoA
    DOI:  https://doi.org/10.1242/jcs.236166
  16. Front Cell Dev Biol. 2021 ;9 634649
    Superresolution Microscopy Reveals Distinct Phosphoinositide Subdomains Within the Cilia Transition Zone.
    Sarah E Conduit, Elizabeth M Davies, Alex J Fulcher, Viola Oorschot, Christina A Mitchell.
      Primary cilia are evolutionary conserved microtubule-based organelles that protrude from the surface of most mammalian cells. Phosphoinositides (PI) are membrane-associated signaling lipids that regulate numerous cellular events via the recruitment of lipid-binding effectors. The temporal and spatial membrane distribution of phosphoinositides is regulated by phosphoinositide kinases and phosphatases. Recently phosphoinositide signaling and turnover has been observed at primary cilia. However, the precise localization of the phosphoinositides to specific ciliary subdomains remains undefined. Here we use superresolution microscopy (2D stimulated emission depletion microscopy) to map phosphoinositide distribution at the cilia transition zone. PI(3,4,5)P3 and PI(4,5)P2 localized to distinct subregions of the transition zone in a ring-shape at the inner transition zone membrane. Interestingly, the PI(3,4,5)P3 subdomain was more distal within the transition zone relative to PtdIns(4,5)P2. The phosphoinositide effector kinase pAKT(S473) localized in close proximity to these phosphoinositides. The inositol polyphosphate 5-phosphatase, INPP5E, degrades transition zone phosphoinositides, however, studies of fixed cells have reported recombinant INPP5E localizes to the ciliary axoneme, distant from its substrates. Notably, here using live cell imaging and optimized fixation/permeabilization protocols INPP5E was found concentrated at the cilia base, in a distribution characteristic of the transition zone in a ring-shaped domain of similar dimensions to the phosphoinositides. Collectively, this superresolution map places the phosphoinositides in situ with the transition zone proteins and reveals that INPP5E also likely localizes to a subdomain of the transition zone membrane, where it is optimally situated to control local phosphoinositide metabolism.
    Keywords:  INPP5E; phosphoinositides; primary cilia; superresolution microscopy; transition zone
    DOI:  https://doi.org/10.3389/fcell.2021.634649
  17. J Cell Sci. 2020 Jan 01. pii: jcs.240648. [Epub ahead of print]
    Epb41l5 interacts with IQCB1 and regulates ciliary function in zebrafish embryos.
    Tiffany Yu, Miho Matsuda.
      Erythrocyte protein band 4.1 like 5 (Epb41l5) is an adaptor protein beneath the plasma membrane that functions to control epithelial morphogenesis. Here we report a previously uncharacterized role of Epb41l5 in controlling ciliary function. We found that Epb41l5 forms a complex with IQCB1/NPHP5, a ciliopathy gene. Epb415 overexpression reduced IQCB1 localization at the ciliary base in cultured epithelial cells. Conversely, epb41l5 knockdown increased IQCB1 localization at the ciliary base. epb41l5-deficient zebrafish embryos or embryos expressing the C-terminally modified forms of Epb41l5 developed cilia with reduced motility and exhibited left-right patterning defects, an outcome of abnormal ciliary function. We observed genetic synergy between epb41l5 and iqcb1. Finally, Epb41l5 decreased IQCB1 interaction with Cep290, another ciliopathy gene and a component of the ciliary base and the centrosome. Together, these observations suggest that Epb41l5 regulates the composition of the ciliary base and the centrosome through IQCB1 and Cep290.
    Keywords:  Cilia; Epb41l5; Epithelial morphogenesis; IQCB1; Left-right patterning; Zebrafish
    DOI:  https://doi.org/10.1242/jcs.240648
  18. J Vis Exp. 2021 May 01.
    Artificial Intelligence Approaches to Assessing Primary Cilia.
    Ruchi Bansal, Staci E Engle, Tisianna K Kamba, Kathryn M Brewer, Wesley R Lewis, Nicolas F Berbari.
      Cilia are microtubule based cellular appendages that function as signaling centers for a diversity of signaling pathways in many mammalian cell types. Cilia length is highly conserved, tightly regulated, and varies between different cell types and tissues and has been implicated in directly impacting their signaling capacity. For example, cilia have been shown to alter their lengths in response to activation of ciliary G protein-coupled receptors. However, accurately and reproducibly measuring the lengths of numerous cilia is a time-consuming and labor-intensive procedure. Current approaches are also error and bias prone. Artificial intelligence (Ai) programs can be utilized to overcome many of these challenges due to capabilities that permit assimilation, manipulation, and optimization of extensive data sets. Here, we demonstrate that an Ai module can be trained to recognize cilia in images from both in vivo and in vitro samples. After using the trained Ai to identify cilia, we are able to design and rapidly utilize applications that analyze hundreds of cilia in a single sample for length, fluorescence intensity and co-localization. This unbiased approach increased our confidence and rigor when comparing samples from different primary neuronal preps in vitro as well as across different brain regions within an animal and between animals. Moreover, this technique can be used to reliably analyze cilia dynamics from any cell type and tissue in a high-throughput manner across multiple samples and treatment groups. Ultimately, Ai-based approaches will likely become standard as most fields move toward less biased and more reproducible approaches for image acquisition and analysis.
    DOI:  https://doi.org/10.3791/62521
  19. J Cell Sci. 2020 Jan 01. pii: jcs.249557. [Epub ahead of print]
    GDNF drives rapid tubule morphogenesis in novel 3D in vitro model for ADPKD.
    Eryn E Dixon, Demetri S Maxim, Victoria L Halperin Kuhns, Allison C Lane-Harris, Patricia Outeda, Andrew J Ewald, Terry J Watnick, Paul A Welling, Owen M Woodward.
      Cystogenesis is a morphological consequence of numerous genetic diseases of the epithelium. In the kidney, the pathogenic mechanisms underlying the program of altered cell and tubule morphology are obscured by secondary effects of cyst expansion. Here, we developed a new 3D tubuloid system to isolate the rapid changes in protein localization and gene expression that correlate with altered cell and tubule morphology during cyst initiation. Mouse renal tubule fragments were pulsed with a cell differentiation cocktail including glial derived neurotrophic factor (GDNF) to yield collecting duct-like tubuloid structures with appropriate polarity, primary cilium, and gene expression. Using the 3D tubuloid model with an inducible Pkd2 knockout system allowed the tracking of morphological, protein, and genetic changes during cyst formation. Within hours of inactivation of Pkd2 and loss of polycystin-2, we observed significant progression in tubuloid to cyst morphology that correlated with 35 differentially expressed genes, many related to cell junctions, matrix interactions, and cell morphology previously implicated in cystogenesis.
    Keywords:  3D cell model; Collecting duct; Epithelia; Kidney; Polycystic kidney disease; Tubulogenesis
    DOI:  https://doi.org/10.1242/jcs.249557
  20. Am J Physiol Lung Cell Mol Physiol. 2021 05 19.
    RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration.
    Debra T Linfield, Nannan Gao, Andjela Raduka, Terri J Harford, Giovanni Piedimonte, Fariba Rezaee.
      The airway epithelium's ability to repair itself after injury, known as epithelial restitution, is an essential mechanism enabling the respiratory tract's normal functions. Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract infections worldwide. We sought to determine whether RSV delays the airway epithelium wound repair process both in vitro and in vivo. We found that RSV infection attenuated epithelial cell migration, a step in wound repair, promoted stress fiber formation, and mediated assembly of large focal adhesions (FA). Inhibition of Rho kinase (ROCK), a master regulator of actin function, reversed these effects. There was increased RhoA and phospho-myosin light chain (pMLC2) following RSV infection. In vivo, mice were intraperitoneally inoculated with naphthalene to induce lung injury, followed by RSV infection. RSV infection delayed re-epithelialization. There were increased concentrations of pMLC2 in day 7 naphthalene plus RSV animals which normalized by day 14. This study suggests a key mechanism by which RSV infection delays wound healing.
    Keywords:  Rho-associated kinase; actin cytoskeleton; epithelial cells; focal adhesion molecules; wound healing
    DOI:  https://doi.org/10.1152/ajplung.00118.2021
  21. Biomed Pharmacother. 2021 May 17. pii: S0753-3322(21)00513-8. [Epub ahead of print]140 111731
    Emerging role of lncRNAs in the regulation of Rho GTPase pathway.
    Soudeh Ghafouri-Fard, Rezvan Noroozi, Atefe Abak, Mohammad Taheri, Alireza Salimi.
      The Ras homolog (Rho) family of small GTPases comprise several proteins with prominent roles in regulation of cell cycle transition, cell migration, and remodeling of actin cytoskeleton. Expression of these proteins is regulated by several factors among them are long non-coding RNAs (lncRNAs). The impact of lncRNAs on Rho GTPases signaling can be exerted through direct modulation of expression of these proteins or influencing expression of miRNAs that negatively regulate Rho GTPases. LINC00974/miR-122/RhoA, MALAT1/miR-429/RhoA, ZFAS1/miR-3924/RhoA/ROCK2, PCAT6/miR-326/RhoA/ROCK, SMILR/miR-141/RhoA/ROCK, DAPK1/miR-182/RhoA, GAS5/miR663a/RhoB, H19/miR-15b/CDC42/PAK1, TDRG1/miR-93/RhoC, TUG1/miR-498/CDC42, UCA1/miR-18a/Cdc42 and UCA1/miR-182/Cdc42 are examples of lncRNAs/miRNAs axes that regulate Rho GTPases. In the present manuscript, we describe the role of lncRNAs on Rho GTPases.
    Keywords:  Expression; Long non-coding RNA; Rho GTPase
    DOI:  https://doi.org/10.1016/j.biopha.2021.111731
  22. MicroPubl Biol. 2021 May 11. 2021
    The IFT20 homolog in Caenorhabditis elegans is required for ciliogenesis and cilia-mediated behavior.
    Ana R G De-Castro, Joana Quintas-Gonçalves, Tiago Silva-Ribeiro, Diogo R M Rodrigues, Maria J G De-Castro, Carla M Abreu, Tiago J Dantas.
      Cilia are microtubule-based organelles that carry out a wide range of critical functions throughout the development of higher animals. Regardless of their type, all cilia rely on a motor-driven, bidirectional transport system known as intraflagellar transport (IFT). Of the many components of the IFT machinery, IFT20 is one of the smallest subunits. Nevertheless, IFT20 has been shown to play critical roles in the assembly of several types of mammalian cilia. Here we show that the IFT20 homolog in Caenorhabditis elegans, IFT-20, is also important for correct cilium assembly in sensory neurons. Strikingly, however, we find that IFT-20-deficient animals are able to assemble short, vestigial cilia. In spite of this, we show that practically all IFT-20-deficient animals fail to respond to environmental cues that are normally detected by cilia to modulate their behavior. Altogether, our results indicate that IFT-20 is critical for both the correct assembly and function of cilia in C. elegans.
    DOI:  https://doi.org/10.17912/micropub.biology.000396
  23. Biol Open. 2020 Jan 01. pii: bio.054338. [Epub ahead of print]
    Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome.
    Anila Iqbal, Marta Baldrighi, Jennifer N Murdoch, Angeleen Fleming, Christopher J Wilkinson.
      Protein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.
    Keywords:  Aggresome; Alpha-synuclein; Centrosome; Cilia; Lewy body; Parkinson's disease
    DOI:  https://doi.org/10.1242/bio.054338
  24. Development. 2020 Jan 01. pii: dev.183301. [Epub ahead of print]
    Ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling.
    Sandii Constable, Alyssa B Long, Katharine A Floyd, Stéphane Schurmans, Tamara Caspary.
      Sonic hedgehog (Shh) signal transduction specifies ventral cell fates in the neural tube and is mediated by the Gli transcription factors that play both activator (GliA) and repressor (GliR) roles. Cilia are essential for Shh signal transduction and the ciliary phosphatidylinositol phosphatase, Inpp5e, is linked to Shh regulation. In the course of a forward genetic screen for recessive mouse mutants, we identified a functional null allele of Inpp5e, ridge top (rdg), with expanded ventral neural cell fates at E10.5. By E12.5, Inpp5erdg/rdg embryos displayed normal neural patterning and this correction over time required Gli3, the predominant repressor in neural patterning. Inpp5erdg function largely depended on the presence of cilia and on Smoothened, the obligate transducer of Shh signaling, indicating Inpp5e functions within the cilium to regulate the pathway. These data indicate that Inpp5e plays a more complicated role in Shh signaling than previously appreciated. We propose that Inpp5e attenuates Shh signaling in the neural tube through regulation of the relative timing of GliA and GliR production, which is important in understanding how duration of Shh signaling regulates neural tube patterning.
    Keywords:  Cilia; Inpp5e; Neural tube patterning; Phosphatidylinositol phosphatase; Sonic hedgehog
    DOI:  https://doi.org/10.1242/dev.183301
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