bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–09–17
nine papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease.
  2. Clinical Characteristics of Rapid Progression in Asia-Pacific Patients With ADPKD.
  3. Identification and Analysis of Primary Cilia in the Corneal Endothelial Cells of Patients with Bullous Keratopathy.
  4. Cold-shock proteins accumulate in centrosomes and their expression and primary cilium morphology are regulated by hypothermia and shear stress.
  5. Integrated modeling of the Nexin-dynein regulatory complex reveals its regulatory mechanism.
  6. The tectonic complex regulates membrane protein composition in the photoreceptor cilium.
  7. Evolution: The ancient history of cilia assembly regulation.
  8. Bilateral cilia incarnata in a breast carcinoma patient receiving Trastuzumab.
  9. Corrigendum: Dendritic cell proliferation by primary cilium in atopic dermatitis.
  1. Sci Transl Med. 2023 Sep 13. 15(713): eabq5930
    A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease.
    Scott H Waddell, Yuelin Yao, Paula Olaizola, Alexander Walker, Edward J Jarman, Konstantinos Gournopanos, Andreea Gradinaru, Ersi Christodoulou, Philippe Gautier, Melissa M Boerrigter, Massimiliano Cadamuro, Luca Fabris, Joost Ph Drenth, Timothy J Kendall, Jesus M Banales, Ava Khamseh, Pleasantine Mill, Luke Boulter.
      The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor-β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery.
    DOI:  https://doi.org/10.1126/scitranslmed.abq5930
  2. Kidney Int Rep. 2023 Sep;8(9): 1801-1810
    Clinical Characteristics of Rapid Progression in Asia-Pacific Patients With ADPKD.
    RAPID-ADPKD Study Group
       Introduction: This study aimed to determine the utility of different methods to predict rapid progressors (RPs) and their clinical characteristics in Asia-Pacific patients with autosomal dominant polycystic kidney disease (ADPKD).
    Methods: This was a multinational retrospective observational cohort study of patients with ADPKD in the Asia-Pacific region. Five hospitals from Australia, China, South Korea, Taiwan, and Turkey participated in this study. RP was defined by European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) guidelines and compared to slow progressors (SPs).
    Results: Among 768 patients, 426 patients were RPs. Three hundred six patients met only 1 criterion and 120 patients satisfied multiple criteria for RP. Historical estimated glomerular filtration rate (eGFR) decline fulfilled the criteria for RP in 210 patients. Five patients met the criteria for a historical increase in height-adjusted total kidney volume (TKV). The 210 patients satisfied the criteria for based on kidney volume. During the follow-up period, cyst infections, cyst hemorrhage, and proteinuria occurred more frequently in RP; and 13.9% and 2.1% of RPs and SPs, respectively, progressed to end-stage kidney disease (ESKD). RP criteria based on historical eGFR decline had the strongest correlation with eGFR change over a 2-year follow-up.
    Conclusion: Various assessment strategies should be used for identifying RPs among Asian-Pacific patients with ADPKD in real-world clinical practice during the follow-up period, cyst infections, cyst hemorrhage, and proteinuria occurred more frequently; and more patients progressed to ESKD in RPs compared with SPs.
    Keywords:  Asia-Pacific region; autosomal dominant polycystic kidney disease; estimated glomerular filtration rate; height-adjusted total kidney volume; rapid progression
    DOI:  https://doi.org/10.1016/j.ekir.2023.06.018
  3. Curr Eye Res. 2023 Sep 14. 1-9
    Identification and Analysis of Primary Cilia in the Corneal Endothelial Cells of Patients with Bullous Keratopathy.
    Hideto Deguchi, Hidetoshi Tanioka, Mako Watanabe, Noriko Horiuchi, Hideki Fukuoka, Osamu Hieda, Tsutomu Inatomi, Shigeru Kinoshita, Chie Sotozono.
       PURPOSE: To identify primary cilia in human corneal endothelial cells (CECs) obtained from patients with bullous keratopathy (BK).
    METHODS: This study involved CEC specimens obtained from 10 eyes of 10 consecutive patients (3 males and 7 females; mean age: 74.5 years, range: 68-90 years) with BK who underwent Descemet's stripping automated endothelial keratoplasty at Baptist Eye Institute, Kyoto, Japan between August 2019 and September 2020. Three corneal buttons obtained from 3 patients who underwent penetrating keratoplasty for keratoconus were used as 'non-BK' controls. All specimens were evaluated with immunofluorescence staining using an antibody against acetylated α-tubulin.
    RESULTS: Ciliary expression was observed in 6 of the 10 CEC specimens; i.e., in 2 specimens obtained from BK patients after glaucoma surgery (trabeculectomy), in 2 specimens obtained from patients with Fuchs endothelial corneal dystrophy, and in 2 specimens obtained from a patient with BK after laser iridotomy for primary angle closure. There was acetylated α-tubulin staining but no hair-like structures in 2 specimens, and ciliary expression was unknown in 2 specimens due to the absence of cells. The length of the primary cilia varied between all specimens. In contrast, no primary cilia were observed in the corneal buttons obtained from the 3 keratoconus patients.
    CONCLUSION: The findings in this study clearly demonstrate the expression of primary cilia in the CECs of patients afflicted with BK.
    Keywords:  DSAEK; bullous keratopathy; corneal endothelial cells; primary cilia
    DOI:  https://doi.org/10.1080/02713683.2023.2259633
  4. Histol Histopathol. 2023 Aug 03. 18656
    Cold-shock proteins accumulate in centrosomes and their expression and primary cilium morphology are regulated by hypothermia and shear stress.
    María Díaz de Cerio, Sara Oliván, Ignacio Ochoa, Josune García-Sanmartín, Alfredo Martínez.
      Primary cilia act as cellular sensors for multiple extracellular stimuli and regulate many intracellular signaling pathways in response. Here we investigate whether the cold-shock proteins (CSPs), CIRP and RBM3, are present in the primary cilia and the physiological consequences of such a relationship. R28, an immortalized retinal precursor cell line, was stained with antibodies against CIRP, RBM3, and ciliary markers. Both CSPs were found in intimate contact with the basal body of the cilium during all stages of the cell cycle, including migrating with the centrosome during mitosis. In addition, the morphological and physiological manifestations of exposing the cells to hypothermia and shear stress were investigated. Exposure to moderately cold (32°C) temperatures, the hypothermia mimetic small molecule zr17-2, or to shear stress resulted in a significant reduction in the number and length of primary cilia. In addition, shear stress induced expression of CIRP and RBM3 in a complex pattern depending on the specific protein, flow intensity, and type of flow (laminar versus oscillatory). Flow-mediated CSP overexpression was detected by qRT-PCR and confirmed by Western blot, at least for CIRP. Furthermore, analysis of public RNA Seq databases on flow experiments confirmed an increase of CIRP and RBM3 expression following exposure to shear stress in renal cell lines. In conclusion, we found that CSPs are integral components of the centrosome and that they participate in cold and shear stress sensing.
    DOI:  https://doi.org/10.14670/HH-18-656
  5. Nat Commun. 2023 Sep 15. 14(1): 5741
    Integrated modeling of the Nexin-dynein regulatory complex reveals its regulatory mechanism.
    Avrin Ghanaeian, Sumita Majhi, Caitlyn L McCafferty, Babak Nami, Corbin S Black, Shun Kai Yang, Thibault Legal, Ophelia Papoulas, Martyna Janowska, Melissa Valente-Paterno, Edward M Marcotte, Dorota Wloga, Khanh Huy Bui.
      Cilia are hairlike protrusions that project from the surface of eukaryotic cells and play key roles in cell signaling and motility. Ciliary motility is regulated by the conserved nexin-dynein regulatory complex (N-DRC), which links adjacent doublet microtubules and regulates and coordinates the activity of outer doublet complexes. Despite its critical role in cilia motility, the assembly and molecular basis of the regulatory mechanism are poorly understood. Here, using cryo-electron microscopy in conjunction with biochemical cross-linking and integrative modeling, we localize 12 DRC subunits in the N-DRC structure of Tetrahymena thermophila. We also find that the CCDC96/113 complex is in close contact with the DRC9/10 in the linker region. In addition, we reveal that the N-DRC is associated with a network of coiled-coil proteins that most likely mediates N-DRC regulatory activity.
    DOI:  https://doi.org/10.1038/s41467-023-41480-7
  6. Nat Commun. 2023 Sep 13. 14(1): 5671
    The tectonic complex regulates membrane protein composition in the photoreceptor cilium.
    Hanh M Truong, Kevin O Cruz-Colón, Jorge Y Martínez-Márquez, Jason R Willer, Amanda M Travis, Sondip K Biswas, Woo-Kuen Lo, Hanno J Bolz, Jillian N Pearring.
      The primary cilium is a signaling organelle with a unique membrane composition maintained by a diffusional barrier residing at the transition zone. Many transition zone proteins, such as the tectonic complex, are linked to preserving ciliary composition but the mechanism remains unknown. To understand tectonic's role, we generate a photoreceptor-specific Tctn1 knockout mouse. Loss of Tctn1 results in the absence of the entire tectonic complex and associated MKS proteins yet has minimal effects on the transition zone structure of rod photoreceptors. We find that the protein composition of the photoreceptor cilium is disrupted as non-resident membrane proteins accumulate in the cilium over time, ultimately resulting in photoreceptor degeneration. We further show that fluorescent rhodopsin moves faster through the transition zone in photoreceptors lacking tectonic, which suggests that the tectonic complex acts as a physical barrier to slow down membrane protein diffusion in the photoreceptor transition zone to ensure proper removal of non-resident membrane proteins.
    DOI:  https://doi.org/10.1038/s41467-023-41450-z
  7. Curr Biol. 2023 Sep 11. pii: S0960-9822(23)00992-2. [Epub ahead of print]33(17): R898-R900
    Evolution: The ancient history of cilia assembly regulation.
    Juliette Azimzadeh, Bénédicte Durand.
      A new study identifies a conserved regulatory mechanism for cilia assembly in the closest unicellular relatives of animals, suggesting that this mechanism was already present in a common unicellular ancestor and was repurposed during the transition to multicellularity.
    DOI:  https://doi.org/10.1016/j.cub.2023.07.053
  8. Clin Exp Optom. 2023 Sep 10. 1
    Bilateral cilia incarnata in a breast carcinoma patient receiving Trastuzumab.
    Niranjana J, Deepsekhar Das, Abhijeet Beniwal.
      
    Keywords:  Bilateral cilia incarnata; Trastuzumab; breast carcinoma
    DOI:  https://doi.org/10.1080/08164622.2023.2243265
  9. Front Mol Biosci. 2023 ;10 1215185
    Corrigendum: Dendritic cell proliferation by primary cilium in atopic dermatitis.
    Manami Toriyama, Defri Rizaldy, Motoki Nakamura, Yukiko Atsumi, Michinori Toriyama, Fumitaka Fujita, Fumihiro Okada, Akimichi Morita, Hiroshi Itoh, Ken J Ishii.
      [This corrects the article DOI: 10.3389/fmolb.2023.1149828.].
    Keywords:  atopic dermatitis; dendritic cell; keratinocytes; langerhans cell; pdgf signaling; primary cilium
    DOI:  https://doi.org/10.3389/fmolb.2023.1215185
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