bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–02–19
fourteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Accuracy and processing time of kidney volume measurement methods in rodent polycystic kidney disease models: superiority of semi-automated kidney segmentation.
  2. Risk Severity Model for Pediatric Autosomal Dominant Polycystic Kidney Disease Using 3D Ultrasound Volumetry.
  3. HOPS-dependent lysosomal fusion controls Rab19 availability for ciliogenesis in polarized epithelial cells.
  4. A targeted multi-proteomics approach generates a blueprint of the ciliary ubiquitinome.
  5. Ciliary ARL13B inhibits developmental kidney cystogenesis in mouse.
  6. Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease.
  7. Primary cilia TRP channels regulate hippocampal excitability.
  8. CEUS utility in the diagnosis of a stage I renal cancer developed on polycystic kidney. A case report.
  9. Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis.
  10. Three-dimensional single-molecule super-resolution imaging of proteins involved in primary cilia formation.
  11. Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1.
  12. A single-molecule view on intraflagellar transport in C. elegans chemosensory cilia.
  13. Human IFT-A complex structures provide molecular insights into ciliary transport.
  14. TTBK2 mutations associated with spinocerebellar ataxia type 11 disrupt peroxisome dynamics and ciliary localization of SHH signaling proteins.
  1. Am J Physiol Renal Physiol. 2023 Feb 16.
    Accuracy and processing time of kidney volume measurement methods in rodent polycystic kidney disease models: superiority of semi-automated kidney segmentation.
    Mary Claire Doss, Sean Mullen, Ronald Roye, Juling Zhou, Phillip Chumley, Elias Mrug, Darren P Wallace, Feng Qian, Peter C Harris, Bradley K Yoder, Harrison Kim, Michal Mrug.
      Measurement of total kidney volume (TKV) using magnetic resonance imaging (MRI) is a valuable approach for monitoring disease progression in autosomal dominant polycystic kidney disease (ADPKD) and is becoming more common in preclinical studies using animal models. Manual contouring of kidney MRI areas (i.e., manual method (MM)) is a conventional, but time-consuming, way to determine TKV. We developed a template-based semi-automatic image segmentation method (SAM) and validated it in three commonly used PKD models, Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck/pck rats (n=10 per model). We compared SAM-based TKV with those obtained by clinical alternatives including the ellipsoid formula-based method (EM) using three kidney dimensions, the longest kidney length method (LM), and the MM, which is considered the gold standard. Both SAM and EM presented high accuracy in TKV assessment in Cys1cpk/cpk mice (interclass correlation coefficient (ICC)≥0.94). SAM was superior to EM and LM in Pkd1RC/RC mice (ICC=0.87, 0.74, and <0.10 for SAM, EM, and LM, respectively) and Pkhd1pck/pck rats (ICC=0.59, <0.10, and <0.10, respectively). Also, SAM outperformed EM in processing time in Cys1cpk/cpk (3.6±0.6 vs 4.4±0.7 minutes per kidney)and Pkd1RC/RC mice (3.1±0.4 vs 7.1±2.6 minutes) (both p<0.001), but not in Pkhd1PCK/PCK rats (3.7±0.8 vs3.2±0.5 minutes). LM was the fastest (~1 min), but correlated most poorly with MM-based TKV in all studied models. Processing times by MM were longer for Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck.pckrats (66.1±7.3, 38.3±7.5, and 29.2±3.5 minutes). In summary, SAM is a fast and accurate method to determine TKV in mouse and rat PKD models.
    Keywords:  Animal models; Cystic kidney disease; Image analysis tools; Inherited kidney disease; Magnetic resonance imaging
    DOI:  https://doi.org/10.1152/ajprenal.00295.2022
  2. Clin J Am Soc Nephrol. 2023 Feb 17.
    Risk Severity Model for Pediatric Autosomal Dominant Polycystic Kidney Disease Using 3D Ultrasound Volumetry.
    CRISP Consortium
       BACKGROUND: Height-adjusted total kidney volume (htTKV) measured by imaging defined as Mayo Imaging Class (MIC) is a validated prognostic measure for autosomal dominant polycystic kidney disease (ADPKD) in adults to predict and stratify disease progression. However, no stratification tool is currently available in pediatric ADPKD. Since magnetic resonance imaging and computed tomography in children are difficult, we propose a novel 3D ultrasound based pediatric Leuven Imaging Classification (LIC) to complement the MIC.
    METHODS: A prospective study cohort of seventy-four genotyped ADPKD patients (37 female) is followed longitudinally with ultrasound including 3D ultrasound and they underwent in total 247 3D ultrasound assessments, with patients' median age (interquartile range) at diagnosis of 3 (0-9) years and at first 3D ultrasound evaluation of 10 (5-14) years with htTKV of 161 (117-208) mL/m. First, data matching was done to the published MIC classification, followed by subsequent optimization of parameters and model type.
    RESULTS: PKD1 was confirmed in 70 patients (95%), PKD2 in three (4%), and GANAB only once (1%). Over these 247 evaluations, the median height was 143 (122-166) cm and total kidney volume was 236 (144-344) mL, leading to an htTKV of 161 (117-208) mL/m. Applying the adult Mayo classification below the age of 15 years strongly underestimated ADPKD severity in children, even with correction for height. We therefore optimized the model with our pediatric data and eventually validated it with data of young patients from Mayo Clinic and the CRISP Consortium used to establish the MIC.
    CONCLUSIONS: We proposed a 5-level "LIC ADPKD Pediatric Model" as a novel classification tool based on patients' age and 3D ultrasound-htTKV for reliable discrimination of childhood ADPKD severity.
    DOI:  https://doi.org/10.2215/CJN.0000000000000122
  3. bioRxiv. 2023 Feb 08. pii: 2023.02.07.527563. [Epub ahead of print]
    HOPS-dependent lysosomal fusion controls Rab19 availability for ciliogenesis in polarized epithelial cells.
    Huxley K Hoffman, Rytis Prekeris.
      Primary cilia are sensory cellular organelles crucial for organ development and homeostasis. Ciliogenesis in polarized epithelial cells requires Rab19-mediated clearing of apical cortical actin to allow the cilium to grow from the apically-docked basal body into the extracellular space. Loss of the lysosomal membrane-tethering HOPS complex disrupts this actin-clearing and ciliogenesis, but it remains unclear how ciliary function of HOPS relates to its canonical function in regulating late endosome-lysosome fusion. Here, we show that disruption of HOPS-dependent lysosomal fusion indirectly impairs actin-clearing and ciliogenesis by disrupting the targeting of Rab19 to the basal body. We also find that Rab19 functions in endolysosomal cargo trafficking apart from its previously-identified role in ciliogenesis. In summary, we show that inhibition of lysosomal fusion abnormally accumulates Rab19 on late endosomes, thus depleting Rab19 from the basal body and thereby disrupting Rab19-mediated actin-clearing and ciliogenesis.
    Summary statement: Loss of HOPS-mediated lysosomal fusion indirectly blocks apical actin clearing and ciliogenesis in polarized epithelia by trapping Rab19 on late endosomes and depleting Rab19 from the basal body.
    DOI:  https://doi.org/10.1101/2023.02.07.527563
  4. Front Cell Dev Biol. 2023 ;11 1113656
    A targeted multi-proteomics approach generates a blueprint of the ciliary ubiquitinome.
    Mariam G Aslanyan, Cenna Doornbos, Gaurav D Diwan, Zeinab Anvarian, Tina Beyer, Katrin Junger, Sylvia E C van Beersum, Robert B Russell, Marius Ueffing, Alexander Ludwig, Karsten Boldt, Lotte B Pedersen, Ronald Roepman.
      Establishment and maintenance of the primary cilium as a signaling-competent organelle requires a high degree of fine tuning, which is at least in part achieved by a variety of post-translational modifications. One such modification is ubiquitination. The small and highly conserved ubiquitin protein possesses a unique versatility in regulating protein function via its ability to build mono and polyubiquitin chains onto target proteins. We aimed to take an unbiased approach to generate a comprehensive blueprint of the ciliary ubiquitinome by deploying a multi-proteomics approach using both ciliary-targeted ubiquitin affinity proteomics, as well as ubiquitin-binding domain-based proximity labelling in two different mammalian cell lines. This resulted in the identification of several key proteins involved in signaling, cytoskeletal remodeling and membrane and protein trafficking. Interestingly, using two different approaches in IMCD3 and RPE1 cells, respectively, we uncovered several novel mechanisms that regulate cilia function. In our IMCD3 proximity labeling cell line model, we found a highly enriched group of ESCRT-dependent clathrin-mediated endocytosis-related proteins, suggesting an important and novel role for this pathway in the regulation of ciliary homeostasis and function. In contrast, in RPE1 cells we found that several structural components of caveolae (CAV1, CAVIN1, and EHD2) were highly enriched in our cilia affinity proteomics screen. Consistently, the presence of caveolae at the ciliary pocket and ubiquitination of CAV1 specifically, were found likely to play a role in the regulation of ciliary length in these cells. Cilia length measurements demonstrated increased ciliary length in RPE1 cells stably expressing a ubiquitination impaired CAV1 mutant protein. Furthermore, live cell imaging in the same cells revealed decreased CAV1 protein turnover at the cilium as the possible cause for this phenotype. In conclusion, we have generated a comprehensive list of cilia-specific proteins that are subject to regulation via ubiquitination which can serve to further our understanding of cilia biology in health and disease.
    Keywords:  ESCRT; caveolae; cilia; cilia ubiquitination; ciliary proteostasis; ciliopathies; clathrin-mediated endocytosis
    DOI:  https://doi.org/10.3389/fcell.2023.1113656
  5. bioRxiv. 2023 Feb 08. pii: 2023.02.08.527739. [Epub ahead of print]
    Ciliary ARL13B inhibits developmental kidney cystogenesis in mouse.
    Robert E Van Sciver, Alyssa B Long, Harrison G Katz, Eduardo D Gigante, Tamara Caspary.
      ARL13B is a small GTPase enriched in cilia. Deletion of Arl13b in mouse kidney results in renal cysts and an associated absence of primary cilia. Similarly, ablation of cilia leads to kidney cysts. To investigate whether ARL13B functions from within cilia to direct kidney development, we examined kidneys of mice expressing an engineered cilia-excluded ARL13B variant, ARL13B V358A . These mice retained renal cilia and developed cystic kidneys. Because ARL13B functions as a guanine nucleotide exchange factor (GEF) for ARL3, we examined kidneys of mice expressing an ARL13B variant that lacks ARL3 GEF activity, ARL13B R79Q . We found normal kidney development with no evidence of cysts in these mice. Taken together, our results show that ARL13B functions within cilia to inhibit renal cystogenesis during mouse development, and that this function does not depend on its role as a GEF for ARL3.
    DOI:  https://doi.org/10.1101/2023.02.08.527739
  6. BMC Nephrol. 2023 Feb 13. 24(1): 33
    Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease.
    Djalila Mekahli, Max C Liebau, Melissa A Cadnapaphornchai, Stuart L Goldstein, Larry A Greenbaum, Mieczyslaw Litwin, Tomas Seeman, Franz Schaefer, Lisa M Guay-Woodford.
       PURPOSE: Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD.
    METHODS: Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307.
    RESULTS: Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation.
    CONCLUSIONS: These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options.
    TRIAL REGISTRATION: Study 204: EudraCT 2020-005991-36; Study 307: EudraCT 2020-005992-10.
    Keywords:  Autosomal recessive polycystic kidney disease (ARPKD); Clinical trial; Efficacy; Pediatric; Safety; Tolvaptan
    DOI:  https://doi.org/10.1186/s12882-023-03072-x
  7. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02716-3. [Epub ahead of print]122(3S1): 321a
    Primary cilia TRP channels regulate hippocampal excitability.
    Thuy Vien, My C Ta, Paul G DeCaen.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1800
  8. Med Ultrason. 2023 Feb 07.
    CEUS utility in the diagnosis of a stage I renal cancer developed on polycystic kidney. A case report.
    Adriana Maria Gomotirceanu, Adina Sabău, Florin Gomotîrceanu, Bogdan Gomotîrceanu, Corina Ioniță, Mirela Liana Gliga.
      We present the case of a 49-year-old patient with polycystic kidney disease in which, in the pre-transplant CT-scan evaluation, a Bosniak III cyst was found in the left kidney. After contrast enhanced ultrasound (CEUS) examination the cyst wasinterpreted as a Bosniak IV malignant cyst and surgical resection of the kidney was realised. The pathology report showed papillary renal cell carcinoma. This case report emphasizes the role of CEUS in polycystic kidney disease examination.
    DOI:  https://doi.org/10.11152/mu-3889
  9. Elife. 2023 Feb 15. pii: e79299. [Epub ahead of print]12
    Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis.
    Emma A Hall, Dhivya Kumar, Suzanna L Prosser, Patricia L Yeyati, Vicente Herranz-Pérez, Jose Manuel García-Verdugo, Lorraine Rose, Lisa McKie, Daniel O Dodd, Peter A Tennant, Roly Megaw, Laura C Murphy, Marisa F Ferreira, Graeme Grimes, Lucy Williams, Tooba Quidwai, Laurence Pelletier, Jeremy F Reiter, Pleasantine Mill.
      Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar Material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. Pcm1-/- mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis. As many of these phenotypes have been observed in human ciliopathies and satellites are implicated in cilia biology, we investigated whether cilia were affected. PCM1 was dispensable for ciliogenesis in many cell types, whereas Pcm1-/- multiciliated ependymal cells and human PCM1-/- retinal pigmented epithelial 1 (RPE1) cells showed reduced ciliogenesis. PCM1-/- RPE1 cells displayed reduced docking of the mother centriole to the ciliary vesicle and removal of CP110 and CEP97 from the distal mother centriole, indicating compromised early ciliogenesis. Similarly, Pcm1-/- ependymal cells exhibited reduced removal of CP110 from basal bodies in vivo. We propose that PCM1 and centriolar satellites facilitate efficient trafficking of proteins to and from centrioles, including the departure of CP110 and CEP97 to initiate ciliogenesis, and that the threshold to trigger ciliogenesis differs between cell types.
    Keywords:  cell biology; developmental biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.79299
  10. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02512-7. [Epub ahead of print]122(3S1): 280a
    Three-dimensional single-molecule super-resolution imaging of proteins involved in primary cilia formation.
    Julia F Love, Saxton D Fisher, Kanie Tomoharu, Anna-Karin Gustavsson, Peter K Jackson.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1596
  11. Am J Physiol Renal Physiol. 2023 Feb 16.
    Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1.
    Jonathan M Shillingford, James A Shayman.
      Polycystic kidney disease is a disorder of renal epithelial growth and differentiation. Transcription factor EB (TFEB), a master regulator of lysosome biogenesis and function, was studied for a potential role in this disorder. The nuclear translocation and functional responses to TFEB activation were studied in three murine models of renal cystic disease, including knockouts of folliculin, folliculin interacting proteins 1 and 2, and Pkd1 as well as in mouse embryonic fibroblasts lacking Pkd1 and 3-dimensional cultures of MDCK cells. Nuclear translocation of Tfeb characterized cystic but not non-cystic renal tubular epithelia in all three murine models as both an early and sustained response to cyst formation. The epithelia expressed elevated levels of Tfeb-dependent gene products, including cathepsin B and Gpnmb. Nuclear Tfeb translocation was observed in mouse embryonic fibroblasts lacking Pkd1, but not wild type fibroblasts. Pkd1 knockout fibroblasts were characterized by increased Tfeb dependent transcripts, lysosomal biogenesis and repositioning, and increased autophagy. The growth of MDCK cell cysts was markedly increased following exposure to the TFEB agonist, compound C1, and nuclear Tfeb translocation was observed in response to both forskolin and compound C1 treatment. Nuclear TFEB also characterized the cystic epithelia but not non-cystic tubular epithelia in human ADPKD patients. The non-canonical activation of TFEB is characteristic of cystic epithelia in multiple models of renal cystic disease including those associated with the loss of Pkd1. Nuclear TFEB translocation is functionally active in these models and may be a component of a general pathway contributing to cystogenesis and growth.
    Keywords:  Autophagic flux; GPNMB; TFEB; lysosome; polycystic kidney
    DOI:  https://doi.org/10.1152/ajprenal.00237.2022
  12. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01178-X. [Epub ahead of print]122(3S1): 5a
    A single-molecule view on intraflagellar transport in C. elegans chemosensory cilia.
    Erwin Peterman.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.262
  13. Cell Res. 2023 Feb 13.
    Human IFT-A complex structures provide molecular insights into ciliary transport.
    Meiqin Jiang, Vivek Reddy Palicharla, Darcie Miller, Sun-Hee Hwang, Hanwen Zhu, Patricia Hixson, Saikat Mukhopadhyay, Ji Sun.
      Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how IFT complexes assemble and mediate cargo transport lacks mechanistic understanding due to missing high-resolution structural information of the holo-complexes. Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0-3.9 Å. IFT-A adopts a "lariat" shape with interconnected core and peripheral subunits linked by structurally vital zinc-binding domains. TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. We also determine the molecular impacts of disease mutations on complex formation and ciliary transport. Our work reveals IFT-A architecture, sheds light on ciliary transport and IFT train formation, and enables the rationalization of disease mutations in ciliopathies.
    DOI:  https://doi.org/10.1038/s41422-023-00778-3
  14. bioRxiv. 2023 Feb 01. pii: 2023.01.31.526333. [Epub ahead of print]
    TTBK2 mutations associated with spinocerebellar ataxia type 11 disrupt peroxisome dynamics and ciliary localization of SHH signaling proteins.
    Jesús Muñoz-Estrada, Abraham V Nguyen, Sarah C Goetz.
      Frameshift mutations in Tau Tubulin Kinase 2 ( TTBK2 ) cause spinocerebellar ataxia type 11 (SCA11), which is characterized by the progressive loss of Purkinje cells and cerebellar atrophy. Previous work showed that these TTBK2 variants generate truncated proteins that interfere with primary ciliary trafficking and with Sonic Hedgehog (SHH) signaling in mice. Nevertheless, the molecular mechanisms underlying the dominant interference of mutations remain unknown. Herein, we discover that SCA11-associated variants contain a bona fide peroxisomal targeting signal type 1. We find that their expression in RPE1 cells reduces peroxisome numbers within the cell and at the base of the cilia, disrupts peroxisome fission pathways, and impairs trafficking of ciliary SMO upon SHH signaling activation. This work uncovers a neomorphic function of SCA11-causing mutations and identifies requirements for both peroxisomes and cholesterol in trafficking of cilia-localized SHH signaling proteins. In addition, we postulate that molecular mechanisms underlying cellular dysfunction in SCA11 converge on the SHH signaling pathway.
    SUMMARY: Molecular mechanisms underlying spinocerebellar ataxia type 11 are not well understood. In this study, we identified a neomorphic function of the mutated gene ( TTBK2 ) associated with this disease highlighting a functional inter-organelle interaction between peroxisomes and cilia.
    DOI:  https://doi.org/10.1101/2023.01.31.526333
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