bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–05–08
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Mechanism of tethered agonist-mediated signaling by polycystin-1.
  2. Comparative analysis of tools to predict rapid progression in autosomal dominant polycystic kidney disease.
  3. Translating Clinical Research to Clinical Care in Nephrology: A Qualitative Study of Nephrology Clinicians.
  4. The retromer complex regulates C. elegans development and mammalian ciliogenesis.
  5. Multidisciplinary management of chronic refractory pain in autosomal dominant polycystic kidney disease.
  6. A cytoplasmic protein kinase couples engagement of Chlamydomonas ciliary receptors to cAMP-dependent cellular responses.
  7. Incidence, Risk Factors and Outcomes of Kidney and Liver Cyst Infection in Kidney Transplant Recipient With ADPKD.
  8. Differential requirements for the Eps15 homology Domain Proteins EHD4 and EHD2 in the regulation of mammalian ciliogenesis.
  9. ROCK 1 and 2 affect the spatial architecture of 3D spheroids derived from human corneal stromal fibroblasts in different manners.
  10. Motor Cooperation During Mitosis and Ciliogenesis.
  11. Atypical Clinical Presentation of Autosomal Recessive Polycystic Kidney Mimicking Medullary Sponge Kidney Disease.
  12. RhoA-ROCK competes with YAP to regulate amoeboid breast cancer cell migration in response to lymphatic-like flow.
  1. Proc Natl Acad Sci U S A. 2022 May 10. 119(19): e2113786119
    Mechanism of tethered agonist-mediated signaling by polycystin-1.
    Shristi Pawnikar, Brenda S Magenheimer, Ericka Nevarez Munoz, Robin L Maser, Yinglong Miao.
      SignificanceMutations of polycystin-1 (PC1) are the major cause (85% of cases) of autosomal dominant polycystic kidney disease (ADPKD), which is the fourth leading cause of kidney failure. PC1 is thought to function as an atypical G protein-coupled receptor, yet the mechanism by which PC1 regulates G-protein signaling remains poorly understood. A significant portion of ADPKD mutations of PC1 encode a protein with defects in maturation or reduced function that may be amenable to functional rescue. In this work, we have combined complementary biochemical and cellular assay experiments and accelerated molecular simulations, which revealed an allosteric transduction pathway in activation of the PC1 C-terminal fragment. Our findings will facilitate future rational drug design efforts targeting the PC1 signaling function.
    Keywords:  Gaussian accelerated molecular dynamics; cellular signaling; mutagenesis; polycystin-1; tethered agonist
    DOI:  https://doi.org/10.1073/pnas.2113786119
  2. Clin Kidney J. 2022 May;15(5): 912-921
    Comparative analysis of tools to predict rapid progression in autosomal dominant polycystic kidney disease.
    Javier Naranjo, Mónica Furlano, Ferran Torres, Jonathan Hernandez, Marc Pybus, Laia Ejarque, Christian Cordoba, Lluis Guirado, Elisabet Ars, Roser Torra.
       Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and shows a wide phenotype. Only patients with rapid progression (RP) are included in clinical trials or are approved to receive disease-modifying drugs. This study aims at comparing different available predictive tools in ADPKD with the Mayo classification (MC) identification of rapid progressors based on high total kidney volume (TKV) according to age.
    Methods: A total of 164 ADPKD patients were recruited retrospectively from a single centre. The performance of diverse tools to identify RP defined as being in MC categories 1C-1E was assessed.
    Results: A total of 118 patients were MC 1C-1E. The algorithm developed by the European Renal Association-European Dialysis and Transplant Association Working Group on Inherited Kidney Disorders/European Renal Best Practice had a low sensitivity in identifying MC 1C-1E. The sensitivity and specificity of TKV to predict RP depend on the cut-off used. A kidney length of >16.5 cm before age 45 years has high specificity but low sensitivity. Assessing the MC by ultrasonography had high levels of agreement with magnetic resonance imaging (MRI) data, especially for 1A, 1D and 1E. The estimated glomerular filtration rate (eGFR) decline was very sensitive but had low specificity. In contrast, the Predicting Renal Outcome in Polycystic Kidney Disease (PROPKD) score was very specific but had poor sensitivity. Having hypertension before 35 years of age is a good clinical predictor of MC 1C-1E. Family history can be of help in suggesting RP, but by itself it lacks sufficient sensitivity and specificity.
    Conclusions: The MC by ultrasonography could be an option in hospitals with limited access to MRI as it performs well generally, and especially at the extremes of the MC, i.e. classes 1A, 1D and 1E. The eGFR decline is sensitive but not very specific when compared with the MC, whereas the PROPKD score is very specific but has low sensitivity. Integrating the different tools currently available to determine RP should facilitate the identification of rapid progressors among patients with ADPKD.
    Keywords:  ADPKD; Mayo classification; PROPKD; prediction; rapid progression; total kidney volume
    DOI:  https://doi.org/10.1093/ckj/sfab293
  3. Kidney Med. 2022 May;4(5): 100459
    Translating Clinical Research to Clinical Care in Nephrology: A Qualitative Study of Nephrology Clinicians.
    Dana Ravyn, Beth Goodwin, Rob Lowney, Arlene Chapman.
       Rationale & Objective: The translation of clinical research to practice has been the subject of intense scrutiny in the efforts to identify ways to improve the uptake of findings that can enhance patient care.
    Study Design: This study evaluated the experience of nephrology health care providers who manage patients with autosomal dominant polycystic kidney disease (ADPKD) to identify promoters and barriers to the translation of research results into clinical practice. We used inductive thematic analysis to evaluate the experience, attitudes, and beliefs of physicians in the evaluation and translation of research findings into clinical practice for the care of patients with ADPKD.
    Setting & Participants: Participants in a continuing education activity on ADPKD volunteered for semistructured interviews exploring their experience translating new knowledge into care for patients with ADPKD. An independent institutional review board (Solutions IRB) found the study to be exempt as an educational survey.
    Analytical Approach: Transcripts were coded and excerpted, and emergent themes and relationships were identified through an analysis performed using Dedoose software. Particular attention was paid to characterizing the facilitators and barriers to research translation at different levels of the health care environment.
    Results: Textual interpretation of data from 13 interviews showed that while well-established barriers to research translation are prevalent among health care providers managing patients with ADPKD, these clinicians also face unique challenges. Principal among these is the burden of interpreting the clinical research literature given the lack of official guidelines.
    Limitations: This study did not explore the translation of all levels of research, such as basic science and animal studies, and it was limited to the translation of knowledge from clinical studies. The number of participants was limited but was found to be sufficient for saturation.
    Conclusions: We identified factors that may either enhance or impede research translation for nephrology health care providers. These observations may help in the design of continuing education interventions to promote innovation.
    Keywords:  Autosomal dominant polycystic kidney disease; continuing education; health care environment; learning theory; nephrology; qualitative analysis; research translation
    DOI:  https://doi.org/10.1016/j.xkme.2022.100459
  4. J Cell Sci. 2022 May 05. pii: jcs.259396. [Epub ahead of print]
    The retromer complex regulates C. elegans development and mammalian ciliogenesis.
    Shuwei Xie, Carter Dierlam, Ellie Smith, Ramon Duran, Allana Williams, Angelina Davis, Danita Mathew, Naava Naslavsky, Jyoti Iyer, Steve Caplan.
      The mammalian retromer consists of subunits VPS26, VPS29 and VPS35, and a loosely-associated sorting nexin (SNX) heterodimer or a variety of other SNX proteins. Despite involvement in yeast and mammalian cell trafficking, retromer's role in development is poorly understood, and its impact on primary ciliogenesis remains unknown. Using CRISPR-Cas9 editing, we demonstrate that vps-26 knockout worms have reduced brood sizes, impaired vulval development, and decreased body length, which have been linked to ciliogenesis defects. While preliminary studies did not identify worm ciliary defects, and impaired development limited additional ciliogenesis studies, we turned to mammalian cells to investigate the role of retromer in ciliogenesis. VPS35 localized to the primary cilium of mammalian cells, and depletion of VPS26, VPS35, VPS29, SNX1, SNX2, SNX5 or SNX27 led to decreased ciliogenesis. Retromer also coimmunoprecipitated with the centriolar protein, CP110, and was required for its removal from the mother centriole. Herein, we characterize new roles for the retromer in C. elegans development and in the regulation of ciliogenesis in mammalian cells, suggesting a novel role for the retromer in CP110 removal from the mother centriole.
    Keywords:  CP110; Centrosome; Ciliogenesis; Retromer; VPS26; VPS35
    DOI:  https://doi.org/10.1242/jcs.259396
  5. Nephrol Dial Transplant. 2022 May 05. pii: gfac158. [Epub ahead of print]
    Multidisciplinary management of chronic refractory pain in autosomal dominant polycystic kidney disease.
    Franka van Luijk, Ron T Gansevoort, Hans Blokzijl, Gerbrand J Groen, Robbert J de Haas, Anna M Leliveld, Esther Meijer, Joke M Perdok, Ruud Stellema, Andreas P Wolff, Niek F Casteleijn.
       BACKGROUND: chronic pain is often difficult to manage in ADPKD patients and sometimes even leads to nephrectomy. We analyzed long-term efficacy of our innovative multidisciplinary protocol to treat chronic refractory pain, and that aims to preserve kidney function by applying among other sequential nerve blocks.
    METHODS: patients were eligible if pain was present ≥ 3 months with a score on a visual analogue scale (VAS) of ≥ 50 out of 100, was negatively affecting quality of life, and if there had been insufficient response to previous therapies, including opioid treatment. Treatment options were in respective order analgesics, cyst aspiration and fenestration, nerve blocks and nephrectomy.
    RESULTS: 101 patients were assessed in our clinic, mean age 50 ± 11 years and 65.3% were females. Eight patients were treated with medication, 6 by cyst aspiration or fenestration, 63 by nerve blocks, whereas 6 received surgery as first treatment option. Overall, 76.9% experienced a positive effect on pain complaints shortly after treatment. VAS score was reduced from 60/100 to 20/100 (p < 0.001) and patients lowered their number of non-opioid and opioid analgesics significantly (p < 0.001, p = 0.006 respectively). A substantial part of the patients (32.6%) needed additional treatment. At the end of follow-up only in 13 patients (12.9%) surgical intervention was necessary: 11 nephrectomies (of which 10 in patients already on kidney function replacement treatment), 1 liver transplantation, 1 partial hepatectomy. After a median follow-up of 4.5 [2.5-5.3] years, 69.0% of the patients still had less pain complaints.
    CONCLUSIONS: these data indicate that our multidisciplinary treatment protocol appears effective in reducing pain in the majority of patients with chronic refractory pain, while postponing or even avoiding in most patients surgical interventions as nephrectomy.
    Keywords:  ADPKD; nephrectomy; nerve block; polycystic kidney disease
    DOI:  https://doi.org/10.1093/ndt/gfac158
  6. J Cell Sci. 2022 May 03. pii: jcs.259814. [Epub ahead of print]
    A cytoplasmic protein kinase couples engagement of Chlamydomonas ciliary receptors to cAMP-dependent cellular responses.
    Mayanka Awasthi, Peeyush Ranjan, Simon Kelterborn, Peter Hegemann, William J Snell.
      The primary cilium is a cellular compartment specialized for receipt of extracellular signals essential for development and homeostasis. Although intraciliary responses to engagement of ciliary receptors are well studied, fundamental questions remain about the mechanisms and molecules that transduce ciliary signals into responses in the cytoplasm. During fertilization in the bi-ciliated alga Chlamydomonas reinhardtii, ciliary adhesion between plus and minus gametes triggers an immediate ∼10-fold increase in cellular cAMP and consequent responses in the cytoplasm required for cell-cell fusion. Here, we identify a new participant in ciliary signaling, Gamete-Specific Protein Kinase (GSPK). GSPK is essential for the adhesion-induced cAMP increase and for rapid gamete fusion. The protein is in the cytoplasm and the entire cellular complement responds to a signal from the cilium by becoming phosphorylated within 1 minute after ciliary receptor engagement. Unlike all other cytoplasmic events in ciliary signaling, GSPK phosphorylation is not responsive to exogenously added cAMP. Thus, during ciliary signaling in Chlamydomonas, a cytoplasmic protein is required to rapidly interpret a still uncharacterized ciliary signal to generate a cytoplasmic response.
    Keywords:  Chlamydomonas; Ciliary signaling pathway; Fertilization; Gamete fusion; Protein Kinase; cAMP
    DOI:  https://doi.org/10.1242/jcs.259814
  7. Kidney Int Rep. 2022 Apr;7(4): 867-875
    Incidence, Risk Factors and Outcomes of Kidney and Liver Cyst Infection in Kidney Transplant Recipient With ADPKD.
    Charles Ronsin, Anis Chaba, Ondrej Suchanek, Jean-Philippe Coindre, Clarisse Kerleau, Claire Garandeau, Aurélie Houzet, Diego Cantarovich, Jacques Dantal, Gilles Blancho, Magali Giral, Grégoire Couvrat-Desvergnes, Simon Ville.
       Introduction: Cyst infection is a known complication of autosomal dominant polycystic kidney disease (ADPKD). Here, we describe incidence, risk factors, clinical presentation, and outcomes of cyst infection in kidney transplant recipient.
    Methods: We conducted a single-center retrospective cohort study of patients with ADPKD with renal allografts between January 1, 2009, and October 31, 2020. Cyst infection diagnosis was based on previously described clinical and radiological criteria, using positron emission tomography when available.
    Results: A total of 296 patients with ADPKD with renal allografts were included, and 21 patients experienced 22 episodes of cyst infection over a median follow-up of 4 (2-7) years. The cumulative incidence rate was 3% at 1 year, 6 % at 5 years, and 12% at 10 years after transplantation. In multivariate analysis, history of cyst infection before transplantation was the only significant risk factor identified to predict the occurrence of cyst infection after kidney transplantation (hazard ratio [HR] 3.47, 95% CI 1.29-9.31). The clinical presentation at diagnosis of cyst infection included isolated fever in 5 (23%) episodes, acute kidney injury in 12 (55%), and severe sepsis/septic shock in 3 (14%) episodes. Among the 16 (73%) episodes with culture positivity, Escherichia coli was the most common pathogen. There was no difference between early (≤1 year after transplantation) and late (>1 year) cyst infection episodes in terms of clinical presentation and outcomes. Cyst infection was significantly associated with graft loss (HR 3.93, 95% CI 1.21-12.80), but no causal relationship could be established.
    Conclusion: Incidence of cyst infection in ADPKD after kidney transplantation is low, history of cyst infection representing the main risk factor.
    Keywords:  autosomal dominant polycystic kidney disease; cyst infection; incidence; kidney transplantation; risk factors
    DOI:  https://doi.org/10.1016/j.ekir.2022.01.1062
  8. Traffic. 2022 May 05.
    Differential requirements for the Eps15 homology Domain Proteins EHD4 and EHD2 in the regulation of mammalian ciliogenesis.
    Tyler Jones, Naava Naslavsky, Steve Caplan.
      The endocytic protein EHD1 controls primary ciliogenesis by facilitating fusion of the ciliary vesicle and by removal of CP110 from the mother centriole. EHD3, the closest EHD1 paralog, has a similar regulatory role, but initial evidence suggested that the other two more distal paralogs, EHD2 and EHD4 may be dispensable for ciliogenesis. Herein, we define a novel role for EHD4, but not EHD2, in regulating primary ciliogenesis. To better understand the mechanisms and differential functions of the EHD proteins in ciliogenesis, we first demonstrated a requirement for EHD1 ATP-binding to promote ciliogenesis. We then identified two sequence motifs that are entirely conserved between EH domains of EHD1, EHD3, and EHD4, but display key amino acid differences within the EHD2 EH domain. Substitution of either P446 or E470 in EHD1 with the aligning S451 or W475 residues from EHD2 was sufficient to prevent rescue of ciliogenesis in EHD1-depleted cells upon reintroduction of EHD1. Overall, our data enhance the current understanding of the EHD paralogs in ciliogenesis, demonstrate a need for ATP-binding, and identify conserved sequences in the EH domains of EHD1, EHD3 and EHD4 that regulate EHD1 binding to proteins and its ability to rescue ciliogenesis in EHD1-depleted cells. This article is protected by copyright. All rights reserved.
    Keywords:  ATP-binding; CP110; EHD1; EHD2; EHD3; EHD4; MICAL-L1; SNAP29; ciliary vesicle; ciliogenesis; distal appendage vesicle; mother centriole; primary cilium
    DOI:  https://doi.org/10.1111/tra.12845
  9. Sci Rep. 2022 May 06. 12(1): 7419
    ROCK 1 and 2 affect the spatial architecture of 3D spheroids derived from human corneal stromal fibroblasts in different manners.
    Yosuke Ida, Araya Umetsu, Masato Furuhashi, Megumi Watanabe, Yuri Tsugeno, Soma Suzuki, Fumihito Hikage, Hiroshi Ohguro.
      The objective of the current study was to examine the roles of ROCK1 and 2 on the spatial architecture of human corneal stroma. We examined the effects of a pan-ROCK inhibitor (pan-ROCK-i), ripasudil, and a ROCK2 inhibitor (ROCK2-i), KD025 on the expression of genes that encode for ECM proteins including collagen (COL) 1, 4, 6, and fibronectin (FN), their regulators, a tissue inhibitor of metalloproteinase (TIMP) 1-4, matrix metalloproteinase (MMP) 2, 9 and 14, and ER stress-related factors of two- and three-dimensional (2D and 3D) cultures of human corneal stroma fibroblasts (HCSFs), and the physical properties of 3D HCSF spheroids. A gene expression analysis using ROCK-is indicated that KD025 (ROCK2 selective ROCK inhibitor) induced more significant changes than Rip (ripasudil, pan-ROCK inhibitor), suggesting that ROCK2 might be more extensively involved in the metabolism of ECM proteins and cell architectures of the 2D cultured HCSFs than ROCK1. In terms of the physical properties, size and stiffness of the 3D HCSFs spheroids, Rip caused a significant enlargement and this enhancement was concentration-dependent while KD025 also exerted a similar but less pronounced effect. In contrast, Rip and KD025 modulated physical stiffness differently, in that Rip caused a substantial decrease and KD025 caused an increase. Such diverse effects between Rip and KD025 were also observed for the gene expressions of ECM proteins, their regulators, and ER-stress related factors. The findings presented herein suggest that the ROCK1 and 2 influence the spatial architecture of 3D HCFS spheroids in different manners.
    DOI:  https://doi.org/10.1038/s41598-022-11407-1
  10. Annu Rev Cell Dev Biol. 2022 May 05.
    Motor Cooperation During Mitosis and Ciliogenesis.
    Guangshuo Ou, Jonathan M Scholey.
      Cilia and mitotic spindles are microtubule (MT)-based, macromolecular machines that consecutively assemble and disassemble during interphase and M phase of the cell cycle, respectively, and play fundamental roles in how eukaryotic cells swim through a fluid, sense their environment, and divide to reproduce themselves. The formation and function of these structures depend on several types of cytoskeletal motors, notably MT-based kinesins and dyneins, supplemented by actin-based myosins, which may function independently or collaboratively during specific steps in the pathway of mitosis or ciliogenesis. System-specific differences in these pathways occur because, instead of conforming to a simple one motor-one function rule, ciliary and mitotic motors can be deployed differently by different cell types. This reflects the well-known influence of natural selection on basic molecular processes, creating diversity at subcellular scales. Here we review our current understanding of motor function and cooperation during the assembly-disassembly, maintenance, and functions of cilia and mitotic spindles. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-cellbio-121420-100107
  11. Kidney Int Rep. 2022 Apr;7(4): 916-919
    Atypical Clinical Presentation of Autosomal Recessive Polycystic Kidney Mimicking Medullary Sponge Kidney Disease.
    Emmanuel Letavernier, Madeline Schwoehrer, Marine Livrozet, Camille Saint-Jacques, Laure Raymond, Radoslava Saraeva, Jean-Philippe Haymann, Vincent Frochot, Michel Daudon, Laurent Mesnard.
      
    DOI:  https://doi.org/10.1016/j.ekir.2021.11.035
  12. FASEB Bioadv. 2022 May;4(5): 342-361
    RhoA-ROCK competes with YAP to regulate amoeboid breast cancer cell migration in response to lymphatic-like flow.
    Amina Mohammadalipour, Miguel F Diaz, Megan Livingston, Adesuwa Ewere, Allen Zhou, Paulina D Horton, Loretta T Olamigoke, John M Lamar, John P Hagan, Hyun J Lee, Pamela L Wenzel.
      Lymphatic drainage generates force that induces prostate cancer cell motility via activation of Yes-associated protein (YAP), but whether this response to fluid force is conserved across cancer types is unclear. Here, we show that shear stress corresponding to fluid flow in the initial lymphatics modifies taxis in breast cancer, whereas some cell lines use rapid amoeboid migration behavior in response to fluid flow, a separate subset decrease movement. Positive responders displayed transcriptional profiles characteristic of an amoeboid cell state, which is typical of cells advancing at the edges of neoplastic tumors. Regulation of the HIPPO tumor suppressor pathway and YAP activity also differed between breast subsets and prostate cancer. Although subcellular localization of YAP to the nucleus positively correlated with overall velocity of locomotion, YAP gain- and loss-of-function demonstrates that YAP inhibits breast cancer motility but is outcompeted by other pro-taxis mediators in the context of flow. Specifically, we show that RhoA dictates response to flow. GTPase activity of RhoA, but not Rac1 or Cdc42 Rho family GTPases, is elevated in cells that positively respond to flow and is unchanged in cells that decelerate under flow. Disruption of RhoA or the RhoA effector, Rho-associated kinase (ROCK), blocked shear stress-induced motility. Collectively, these findings identify biomechanical force as a regulator amoeboid cell migration and demonstrate stratification of breast cancer subsets by flow-sensing mechanotransduction pathways.
    Keywords:  ECM–receptor interactions; actomyosin cytoskeleton; biomechanical force; hippo; mechanotransduction; motility; shear stress
    DOI:  https://doi.org/10.1096/fba.2021-00055
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