bims-bicyki 2023-04-23 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2023–04–23
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Comments on the consensus document on autosomal dominant polycystic kidney disease of the SENefro.
Neuronal primary cilia integrate peripheral signals with metabolic drives.
Hypoxia-Inducible Factor-2alpha Affects the MEK/ERK Signaling Pathway via Primary Cilia in Connection with the Intraflagellar Transport Protein 88 Homolog.
Primary cilia as dynamic and diverse signalling hubs in development and disease.
EHD1 promotes CP110 ubiquitination by centriolar satellite delivery of HERC2 to the mother centriole.
Molecular diagnostic results of a nephropathy gene panel in patients with suspected hereditary kidney disease.
Determinants of cytoplasmic microtubule reorganization during ciliogenesis in Chlamydomonas reinhardtii.
Control of centrosome distal appendages assembly and disassembly.
Urinary exosome proteomic profiling defines stage-specific rapid progression of autosomal dominant polycystic kidney disease and tolvaptan efficacy.
Native doublet microtubules from Tetrahymena thermophila reveal the importance of outer junction proteins.
Cystic kidney diseases in children.
Gene augmentation of LCA5-Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme.

Nefrologia (Engl Ed). 2023 Apr 15. pii: S2013-2514(23)00060-3. [Epub ahead of print]

Comments on the consensus document on autosomal dominant polycystic kidney disease of the SENefro.

José Ignacio Minguela.

DOI: https://doi.org/10.1016/j.nefroe.2023.03.006
Front Physiol. 2023 ;14 1150232

Neuronal primary cilia integrate peripheral signals with metabolic drives.

Kelly M DeMars, Madeleine R Ross, Alana Starr, Jeremy C McIntyre.

  Neuronal primary cilia have recently emerged as important contributors to the central regulation of energy homeostasis. As non-motile, microtubule-based organelles, primary cilia serve as signaling antennae for metabolic status. The impairment of ciliary structure or function can produce ciliopathies for which obesity is a hallmark phenotype and global ablation of cilia induces non-syndromic adiposity in mouse models. This organelle is not only a hub for metabolic signaling, but also for catecholamine neuromodulation that shapes neuronal circuitry in response to sensory input. The objective of this review is to highlight current research investigating the mechanisms of primary cilium-regulated metabolic drives for maintaining energy homeostasis.

Keywords:  BBSome; hypothalamus; intraflagellar transport; metabolism; obesity; primary cilium

DOI:  https://doi.org/10.3389/fphys.2023.1150232
Mol Cell Biol. 2023 Apr 19. 1-10

Hypoxia-Inducible Factor-2alpha Affects the MEK/ERK Signaling Pathway via Primary Cilia in Connection with the Intraflagellar Transport Protein 88 Homolog.

Tristan Leu, Jannik Denda, Anna Wrobeln, Joachim Fandrey.

  The ability of cells to communicate with their surrounding is a prerequisite for essential processes such as proliferation, apoptosis, migration, and differentiation. To this purpose, primary cilia serve as antennae-like structures on the surface of most mammalian cell types. Cilia allow signaling via hedgehog, Wnt or TGF-beta pathways. Their length, in part controlled by the activity of intraflagellar transport (IFT), is a parameter for adequate function of primary cilia. Here we show, in murine neuronal cells, that intraflagellar transport protein 88 homolog (IFT88) directly interacts with the hypoxia-inducible factor-2α (HIF-2α), hitherto known as an oxygen-regulated transcription factor. Furthermore, HIF-2α accumulates in the ciliary axoneme and promotes ciliary elongation under hypoxia. Loss of HIF-2α affected ciliary signaling in neuronal cells by decreasing transcription of Mek1/2 and Erk1/2. Targets of the MEK/ERK signaling pathway, such as Fos and Jun, were significantly decreased. Our results suggest that HIF-2α influences ciliary signaling by interacting with IFT88 under hypoxic conditions. This implies an unexpected and far more extensive function of HIF-2α than described before.

Keywords:  HIF-2; IFT88; MEK/ERK signaling; primary cilia

DOI:  https://doi.org/10.1080/10985549.2023.2198931
Nat Rev Genet. 2023 Apr 18.

Primary cilia as dynamic and diverse signalling hubs in development and disease.

Pleasantine Mill, Søren T Christensen, Lotte B Pedersen.

Primary cilia, antenna-like sensory organelles protruding from the surface of most vertebrate cell types, are essential for regulating signalling pathways during development and adult homeostasis. Mutations in genes affecting cilia cause an overlapping spectrum of >30 human diseases and syndromes, the ciliopathies. Given the immense structural and functional diversity of the mammalian cilia repertoire, there is a growing disconnect between patient genotype and associated phenotypes, with variable severity and expressivity characteristic of the ciliopathies as a group. Recent technological developments are rapidly advancing our understanding of the complex mechanisms that control biogenesis and function of primary cilia across a range of cell types and are starting to tackle this diversity. Here, we examine the structural and functional diversity of primary cilia, their dynamic regulation in different cellular and developmental contexts and their disruption in disease.

DOI: https://doi.org/10.1038/s41576-023-00587-9
EMBO Rep. 2023 Apr 19. e56317

EHD1 promotes CP110 ubiquitination by centriolar satellite delivery of HERC2 to the mother centriole.

Shuwei Xie, Naava Naslavsky, Steve Caplan.

  Primary cilia are sensory organelles that coordinate diverse signaling pathways, controlling development and homeostasis. Progression beyond the early steps of ciliogenesis requires the removal of a distal end protein, CP110, from the mother centriole, a process mediated by Eps15 Homology Domain protein 1 (EHD1). We show that EHD1 regulates CP110 ubiquitination during ciliogenesis, and identify two E3 ubiquitin ligases, HECT domain and RCC1-like domain 2 (HERC2) and mindbomb homolog 1 (MIB1), that interact with and ubiquitinate CP110. We determined that HERC2 is required for ciliogenesis and localizes to centriolar satellites, which are peripheral aggregates of centriolar proteins known to regulate ciliogenesis. We reveal a role for EHD1 in the transport of centriolar satellites and HERC2 to the mother centriole during ciliogenesis. Taken together, our work showcases a mechanism whereby EHD1 controls centriolar satellite movement to the mother centriole, thus delivering the E3 ubiquitin ligase HERC2 to promote CP110 ubiquitination and degradation.

Keywords:  CP110; EHD1; HERC2; centriolar satellites; ubiquitination

DOI:  https://doi.org/10.15252/embr.202256317
Lab Med. 2023 Apr 20. pii: lmad027. [Epub ahead of print]

Molecular diagnostic results of a nephropathy gene panel in patients with suspected hereditary kidney disease.

Ali Topak.

   OBJECTIVE: Clinical diagnosis of hereditary kidney disease can be difficult because of its rarity and severe phenotypic variability. Identifying mutated causative genes can provide diagnostic and prognostic information. In this study, we report the clinical application and outcome of a next-generation sequencing-based, targeted multi-gene panel test for the genetic diagnosis of patients with hereditary kidney disease.
METHODS: A total of 145 patients evaluated for hereditary kidney disease who underwent a nephropathy panel with 44 different genes were retrospectively reviewed and included in the study.
RESULTS: Genetic diagnosis of other hereditary kidney diseases, particularly autosomal dominant polycystic kidney disease, was made in 48% of patients. The nephropathy panel changed the preliminary diagnosis in 6% of patients. The variants in 18 (12%) patients had not been previously reported in the literature.
CONCLUSION: This study demonstrates the utility of the nephropathy panel in identifying patients diagnosed with hereditary kidney disease who are referred for genetic testing. A contribution was made to the variant spectrum of genes associated with hereditary kidney disease.

Keywords:  NGS; hereditary; kidney disease; nephropathy; novel; polycystic

DOI:  https://doi.org/10.1093/labmed/lmad027
bioRxiv. 2023 Apr 07. pii: 2023.04.07.536038. [Epub ahead of print]

Determinants of cytoplasmic microtubule reorganization during ciliogenesis in Chlamydomonas reinhardtii.

Larissa L Dougherty, Prachee Avasthi.

At the core of cilia are microtubules which are important for establishing length and assisting ciliary assembly and disassembly; however, another role for microtubule regulation on ciliogenesis lies outside of the cilium. The microtubule cytoskeleton is a highly dynamic structure which reorganizes rapidly to assist in cellular processes. Cytoplasmic microtubule dynamics have previously been thought to be necessary to free up tubulin and proteins in the ciliary precursor pool for ciliogenesis. However, we previously found that low concentrations of taxol can stabilize cytoplasmic microtubules during deciliation while allowing normal cilium regrowth. Here we look at the relationship between ciliogenesis and cytoplasmic microtubule dynamics in Chlamydomonas reinhardtii using chemical and mechanical perturbations. We find that not only can stabilized cytoplasmic microtubules allow for normal ciliary assembly, but high calcium concentrations and low pH-induced deciliation cause microtubules to depolymerize separately from ciliary shedding. In addition, we find that through mechanical shearing, cilia regenerate more quickly despite intact cytoplasmic microtubules. Our data suggests that cytoplasmic microtubules are not a sink for a limiting pool of cytoplasmic tubulin, reorganization that occurs following deciliation is a consequence rather than a requirement for ciliogenesis, and intact microtubules in the cytoplasm and the proximal cilium support more efficient ciliary assembly.

DOI: https://doi.org/10.1101/2023.04.07.536038
Cells Dev. 2023 Apr 14. pii: S2667-2901(23)00015-3. [Epub ahead of print] 203839

Control of centrosome distal appendages assembly and disassembly.

Johanna M S Streubel, Gislene Pereira.

  Centrosomes are microtubule organizing centers involved in chromosome segregation, spindle orientation, cell motility and cilia formation. In recent years, they have also emerged as key modulators of asymmetric cell division. Centrosomes are composed of two centrioles that initiate duplication in S phase. The conservative nature of centriole duplication means that the two centrioles of a G1 cell are of different ages. They are also structurally different as only the older centriole carry appendages, an assembly of a subset of proteins primarily required for cilia formation. In a growing tissue, the non-motile, primary cilium acts as a mechano- and sensory organelle that influences cell behavior via modulation of signaling pathways. Here, we discuss the most recent findings about distal appendage composition and function, as well as cell cycle-specific regulation and their implications in various diseases.

Keywords:  Basal body; Cell cycle; Centriole maturation; Centrosome; Cilia; Distal appendages; NEK2; PLK1

DOI:  https://doi.org/10.1016/j.cdev.2023.203839
BBA Adv. 2021 ;1 100013

Urinary exosome proteomic profiling defines stage-specific rapid progression of autosomal dominant polycystic kidney disease and tolvaptan efficacy.

Katie L Raby, Harry Horsely, Aidan McCarthy-Boxer, Jill T Norman, Patricia D Wilson.

  ADPKD is the most common genetic disease of the kidney leading to end-stage renal disease necessitating renal replacement therapy at any time between the 1st and 8th decades of life due to widely variable rates of disease progression. This presents significant patient anxiety and a significant prognostic and therapeutic challenge. Tolvaptan is the only approved drug licensed to slow ADPKD progression by reducing renal cystic expansion but side-effects can limit its efficacy. To address the need to identify new biomarkers to monitor progression of ADPKD and to evaluate the therapeutic effects of Tolvaptan, proteomic analysis was conducted on defined (40-100nm) urinary exosomes isolated from ADPKD patients phenotyped and clinically monitored over a 10-year period. Comparative Gene Ontology analysis of Tandem Mass Tag labelled mass spectrometry-derived protein profiles from urinary exosomes from ADPKD patients with rapid (>10ml/min/5 years decline in estimated glomerular filtration rate) versus slow progression showed distinctive patterns of pathway up-regulation. Clear discrimination between rapid and slowly-progressive profiles were seen in all stages functional decline in ADPKD patients whether with mild (>70ml/min), moderate (50-69ml/min) or severe (<49ml/min) disease at onset. Discriminatory pathways and proteins included Notch-, integrin- and growth factor-signalling; microtubular kinase, vesicular proteins and epidermal growth factor substrates. Confocal microscopy of fluorescently-labelled normal versus ADPKD epithelial cell-derived exosomes in vitro also identified ADPKD-dependent abnormalities in intracellular vesicular trafficking and implicated changes in ADPKD-dependent exosome secretion and target cell uptake as factors underlying urinary exosome excretion biomarker properties. Comparative proteomic analysis of urinary exosomal proteins in individual patients before and after treatment with Tolvaptan for 4 years also identified distinct patterns of pathway modification dependent on the degree of effectiveness of the therapeutic response. Up-regulation of Wnt-pathway and vesicular proteins were characteristic of urinary exosomes from ADPKD patients with good responses to Tolvaptan while upregulation of angiogenesis pathways and additional molecular forms of vasopressin receptor AVPR2 were characteristic in urinary exosomes of ADPKD patients with poor responses. Taken together, these studies conclude that proteomic profiling of urinary exosome biomarkers provides a specific, sensitive and practical non-invasive method to identify and monitor the rate of disease progression and the effects of Tolvaptan therapy in individual ADPKD patients. This provides a means to identify those patients most likely to benefit maximally from therapy and to progress towards a personalization of ADPKD prognosis and management.

Keywords:  ADPKD progression; Exosomes; Proteomics; Tolvaptan effects; Urinary biomarkers; Vesicular trafficking

DOI:  https://doi.org/10.1016/j.bbadva.2021.100013
Nat Commun. 2023 04 15. 14(1): 2168

Native doublet microtubules from Tetrahymena thermophila reveal the importance of outer junction proteins.

Shintaroh Kubo, Corbin S Black, Ewa Joachimiak, Shun Kai Yang, Thibault Legal, Katya Peri, Ahmad Abdelzaher Zaki Khalifa, Avrin Ghanaeian, Caitlyn L McCafferty, Melissa Valente-Paterno, Chelsea De Bellis, Phuong M Huynh, Zhe Fan, Edward M Marcotte, Dorota Wloga, Khanh Huy Bui.

Cilia are ubiquitous eukaryotic organelles responsible for cellular motility and sensory functions. The ciliary axoneme is a microtubule-based cytoskeleton consisting of two central singlets and nine outer doublet microtubules. Cryo-electron microscopy-based studies have revealed a complex network inside the lumen of both tubules composed of microtubule-inner proteins (MIPs). However, the functions of most MIPs remain unknown. Here, we present single-particle cryo-EM-based analyses of the Tetrahymena thermophila native doublet microtubule and identify 42 MIPs. These data shed light on the evolutionarily conserved and diversified roles of MIPs. In addition, we identified MIPs potentially responsible for the assembly and stability of the doublet outer junction. Knockout of the evolutionarily conserved outer junction component CFAP77 moderately diminishes Tetrahymena swimming speed and beat frequency, indicating the important role of CFAP77 and outer junction stability in cilia beating generation and/or regulation.

DOI: https://doi.org/10.1038/s41467-023-37868-0
Arch Pediatr. 2023 Apr 14. pii: S0929-693X(23)00031-3. [Epub ahead of print]

Cystic kidney diseases in children.

J De Groof, A Dachy, L Breysem, D Mekahli.

  Cystic kidney disease comprises a broad group of heterogeneous diseases, which differ greatly in age at onset, disease manifestation, systemic involvement, disease progression, and long-term prognosis. As our understanding of these diseases continues to evolve and new treatment strategies continue to emerge, correctly differentiating and diagnosing these diseases becomes increasingly important. In this review, we aim to highlight the key features of the most relevant cystic kidney diseases, underscore important diagnostic characteristics of each disease, and present specific management options if applicable.

Keywords:  ADPKD; ARPDK; Bardet–Biedl syndrome; Cystic dysplasia; HNF1-beta; Kidney cyst; Multicystic dysplastic kidney; Nephronophthisis; Simple kidney cyst; tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.arcped.2023.02.005
JCI Insight. 2023 Apr 18. pii: e169162. [Epub ahead of print]

Gene augmentation of LCA5-Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme.

Siebren Faber, Olivier Mercey, Katrin Junger, Alejandro Garanto, Marius Ueffing, Rob Wj Collin, Karsten Boldt, Paul Guichard, Virginie Hamel, Ronald Roepman.

  Leber congenital amaurosis (LCA) is a group of inherited retinal diseases (IRDs) characterized by the early onset and rapid loss of photoreceptor cells. Despite the discovery of a growing number of genes associated with this disease, the molecular mechanisms of photoreceptor cell degeneration of most LCA subtypes remain poorly understood. Here, using retina-specific affinity proteomics combined with ultrastructure expansion microscopy (U-ExM), we reveal the structural and molecular defects underlying LCA type 5 (LCA5) with nanoscale resolution. We show that LCA5-encoded lebercilin, together with retinitis pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, localize at the bulge region of the photoreceptor outer segment (OS), a region crucial for OS membrane disc formation. Next, we demonstrate that mutant mice deficient for lebercilin exhibit early axonemal defects at the bulge region and the distal OS, accompanied by reduced levels of RP1 and IFT proteins, affecting membrane disc formation and presumably leading to photoreceptor death. Finally, AAV-based LCA5 gene augmentation partially restores the bulge region, preserves OS axoneme structure and membrane disc formation, and results in photoreceptor cell survival. Our approach thus provides a next level of assessment of retinal (gene) therapy efficacy at the molecular level.

Keywords:  Cell Biology; Gene therapy; Genetics; Molecular genetics; Retinopathy

DOI:  https://doi.org/10.1172/jci.insight.169162