bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2020‒11‒01
ten papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)


  1. Prim Care. 2020 Dec;pii: S0095-4543(20)30064-6. [Epub ahead of print]47(4): 673-689
    Perumareddi P, Trelka DP.
      Autosomal Dominant Polycystic Kidney Disease is an inherited multisystemic disorder of the renal tubules with subsequent formation of multiple cysts and enlargement of the kidney, affecting various organs. Diagnosis is initially suspected in those with family history and/or individuals who develop hypertension early on (secondary hypertension) or certain symptoms. Renal function is initially preserved for years secondary to compensatory mechanisms. Associated conditions include: liver cysts, berry aneurysms, kidney stones, etc. The disease course is variable, but patients often progress to end-stage renal failure by age 60. There is no known cure, however, risk factor modification at early stages is critical. Renal transplant is the optimal treatment in ESRD.
    Keywords:  Berry aneurysm; Dialysis; End-stage renal disease; Hematuria; Liver cysts; Polycystic kidney disease; Secondary hypertension; Transplant
    DOI:  https://doi.org/10.1016/j.pop.2020.08.010
  2. Sci Adv. 2020 Oct;pii: eabb3154. [Epub ahead of print]6(44):
    Li LX, Zhou JX, Wang X, Zhang H, Harris PC, Calvet JP, Li X.
      Dysregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) by unknown mechanisms is highly prevalent in human disease. In this study, we identify direct cross-talk between CDK4/6 and the epigenome via its previously unidentified substrate, SMYD2, a histone/lysine methyltransferase. CDK4/6 positively regulates the phosphorylation and enzymatic activity of SMYD2, while SMYD2 also positively regulates the expression of CDK4/6. We also identify SMYD2 as an α-tubulin methyltransferase, thus connecting CDK4/6-SMYD2 signaling to microtubule dynamics. In addition, depletion or inhibition of CDK4/6 and SMYD2 resulted in increased cilia assembly by affecting (i) microtubule stability and (ii) the expression of IFT20, further connecting CDK4/6-SMYD2 to ciliogenesis. In clinical settings such as breast cancer and autosomal dominant polycystic kidney disease (ADPKD), targeting the up-regulated CDK4/6 and SMYD2 with inhibitors results in restoration of the primary cilium in tumor and cystic cells, which may normalize cilia-mediated extracellular signals that regulate growth, development, and cellular homeostasis.
    DOI:  https://doi.org/10.1126/sciadv.abb3154
  3. Proc Natl Acad Sci U S A. 2020 Oct 29. pii: 202009334. [Epub ahead of print]
    Lee EJ, Seo E, Kim JW, Nam SA, Lee JY, Jun J, Oh S, Park M, Jho EH, Yoo KH, Park JH, Kim YK.
      Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1-TAZ-Wnt-β-catenin-c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.
    Keywords:  TAZ; c-myc; polycystic kidney
    DOI:  https://doi.org/10.1073/pnas.2009334117
  4. J Fam Pract. 2020 Sep;69(7 Suppl): S57-S62
    Weir M.
      After reading this review article on ADPKD, participants should be able to: Identify people at high risk for ADPKD. Conduct a diagnostic evaluation. Initiate evidence-based therapy to slow kidney progression and treat extra-renal manifestations.
  5. J Cell Mol Med. 2020 Oct 28.
    Dafinger C, Mandel AM, Braun A, Göbel H, Burgmaier K, Massella L, Mastrangelo A, Dötsch J, Benzing T, Weimbs T, Schermer B, Liebau MC.
      Autosomal recessive polycystic kidney disease (ARPKD) is mainly caused by variants in the PKHD1 gene, encoding fibrocystin (FC), a large transmembrane protein of incompletely understood cellular function. Here, we show that a C-terminal fragment of human FC can suppress a signalling module of the kinase SRC and signal transducer and activator of transcription 3 (STAT3). Consistently, we identified truncating genetic variants specifically affecting the cytoplasmic tail in ARPKD patients, found SRC and the cytoplasmic tail of fibrocystin in a joint dynamic protein complex and observed increased activation of both SRC and STAT3 in cyst-lining renal epithelial cells of ARPKD patients.
    Keywords:  cilia; genetic kidney diseases; polycystic kidney disease
    DOI:  https://doi.org/10.1111/jcmm.16014
  6. Clin Genet. 2020 Oct 27.
    Shi H, Niu W, Liu Y, Jin H, Song W, Shi S, Yao G, Xu J, Sun Y.
      Autosomal dominant hereditary polycystic kidney disease (ADPKD) is the most common inherited kidney disease that causes end-stage renal disease and kidney failure. Preimplantation genetic testing for monogenic (PGT-M) can effectively prevent the transmission of genetic diseases from parents to the offspring before pregnancy. However, PGT-M currently adopts the SNP linkage analysis for embryo's pathogenic gene carrying status and linkage analysis requires proband of the family. Here we report a new PGT-M strategy using single sperm SNP linkage analysis for male patient with sporadic ADPKD caused by de novo PKD1 mutation. This article is protected by copyright. All rights reserved.
    Keywords:  ADPKD; PGT-M; SNP; linkage analysis; single sperm
    DOI:  https://doi.org/10.1111/cge.13871
  7. Sci Adv. 2020 Oct;pii: eabc1799. [Epub ahead of print]6(44):
    Fang F, Schwartz AG, Moore ER, Sup ME, Thomopoulos S.
      The tendon enthesis is a fibrocartilaginous tissue critical for transfer of muscle forces to bone. Enthesis pathologies are common, and surgical repair of tendon to bone is plagued by high failure rates. At the root of these failures is a gap in knowledge of how the tendon enthesis is formed and maintained. We tested the hypothesis that the primary cilium is a hub for transducing biophysical and hedgehog (Hh) signals to regulate tendon enthesis formation and adaptation to loading. Primary cilia were necessary for enthesis development, and cilia assembly was coincident with Hh signaling and enthesis mineralization. Cilia responded inversely to loading; increased loading led to decreased cilia and decreased loading led to increased cilia. Enthesis responses to loading were dependent on Hh signaling through cilia. Results imply a role for tendon enthesis primary cilia as mechanical responders and Hh signal transducers, providing a therapeutic target for tendon enthesis pathologies.
    DOI:  https://doi.org/10.1126/sciadv.abc1799
  8. Front Pharmacol. 2020 ;11 585633
    Matoba K, Takeda Y, Nagai Y, Sekiguchi K, Yokota T, Utsunomiya K, Nishimura R.
      Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase that was originally identified as RhoA interacting protein. A diverse array of cellular functions, including migration, proliferation, and phenotypic modulation, are orchestrated by ROCK through a mechanism involving cytoskeletal rearrangement. Mammalian cells express two ROCK isoforms: ROCK1 (Rho-kinase β/ROKβ) and ROCK2 (Rho-kinase α/ROKα). While both isoforms have structural similarities and are widely expressed across multiple tissues, investigations in gene knockout animals and cell-based studies have revealed distinct functions of ROCK1 and ROCK2. With respect to the kidney, inhibiting ROCK activity has proven effective for the preventing diabetic kidney disease (DKD) in both type 1 and type 2 diabetic rodent models. However, despite significant progress in the understanding of the renal ROCK biology over the past decade, the pathogenic roles of the ROCK isoforms is only beginning to be elucidated. Recent studies have demonstrated the involvement of renal ROCK1 in mitochondrial dynamics and cellular transdifferentiation, whereas ROCK2 activation leads to inflammation, fibrosis, and cell death in the diabetic kidney. This review provides a conceptual framework for dissecting the molecular underpinnings of ROCK-driven renal injury, focusing on the differences between ROCK1 and ROCK2.
    Keywords:  ROCK1/ROCK2; Rho (Rho GTPase); diabetic kidney disease (DKD); hypoxia; inflammation; notch
    DOI:  https://doi.org/10.3389/fphar.2020.585633
  9. J Mol Cell Biol. 2020 Oct 30. pii: mjaa060. [Epub ahead of print]
    Wu Q, Shou J.
      Ever since gene targeting or specific modification of genome sequences in mice was achieved in the early 1980s, the reverse genetic approach of precise editing of any genomic locus has greatly accelerated biomedical research and biotechnology development. In particular, the recent development of the CRISPR/Cas9 system has greatly expedited genetic dissection of three-dimensional (3D) genomes. CRISPR gene editing results from targeted genome cleavage by ectopic bacterial Cas9 nuclease followed by presumed random ligations via the host double-strand break (DSB) repair machineries. Recent studies revealed, however, that the CRISPR genome editing system is precise and predictable because of cohesive Cas9 cleavage of targeting DNA. Here, we synthesize the current understanding of CRISPR DNA fragment editing mechanisms and recent progress in predictable outcomes from precise genetic engineering of 3D genomes. Specifically, we first briefly describe historical genetic studies leading to CRISPR and 3D genome engineering. We then summarize different types of chromosomal rearrangements by DNA fragment editing. Finally, we review significant progress from precise one-dimensional (1D) gene editing toward predictable 3D genome engineering and synthetic biology. The exciting and rapid advances in this emerging field provide new opportunities and challenges to understand or digest 3D genomes.
    Keywords:  3D genome engineering; CRISPR; DNA fragment editing; chromatin loops; precision modifications; predictable indels; repair mechanisms
    DOI:  https://doi.org/10.1093/jmcb/mjaa060
  10. FASEB J. 2020 Oct 30.
    Palander O, Trimble WS.
      Primary cilia are critical hubs for several signaling pathways, and defects in ciliogenesis or cilia maintenance produce a range of diseases collectively known as ciliopathies. Ciliogenesis requires vesicle trafficking along a network of microtubules and actin filaments to the basal body. The DIAPH1 (Diaphanous-related formin) family of formins promotes both actin polymerization and EB1-dependent microtubule (MT) stability. EB1 and EB3 have previously been implicated in cilia biogenesis to carry out centrosome-related functions. However, the role of DIAPH1 proteins had not been examined. Here we show that the depletion of DIAPH1 decreased ciliogenesis, cilia length, and reduced trafficking within cilia. Additionally, both actin nucleating and microtubule-stabilizing properties of DIAPH1 are important for their cilia functions. To assess their roles in ciliogenesis in isolation, we targeted DIAPH1 specifically to the basal body, which caused an increase in cilia length and increased trafficking within cilia. Intriguingly, expression of DIAPH1 mutants associated with human deafness and microcephaly impaired ciliation and caused cilia elongation and bulb formation. These results suggest that the actin and microtubule functions of DIAPH1 proteins regulate cilia maintenance in part by regulating vesicular trafficking to the base of the primary cilia.
    Keywords:  (3-5): DIAPH1; ciliogenesis; formin; intraflagellar transport; primary cilia
    DOI:  https://doi.org/10.1096/fj.202001178R