bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023‒03‒19
fifteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. What Is Autosomal Dominant Polycystic Kidney Disease?
  2. Genetic autopsy and genetic counseling for a case of fatal oligohydramnios due to de novo 17q12 deletion syndrome.
  3. Septin-mediated RhoA activation engages the exocyst complex to recruit the cilium transition zone.
  4. Clinical Implementation of an Artificial Intelligence Algorithm for Magnetic Resonance-Derived Measurement of Total Kidney Volume.
  5. The impact of pre-transplantation nephrectomy on quality of life in patients with autosomal dominant polycystic kidney disease.
  6. Structural insight into the intraflagellar transport complex IFT-A and its assembly in the anterograde IFT train.
  7. The association of urinary epidermal growth factors with ADPKD disease severity and progression.
  8. Structure of the N-terminal coiled-coil domains of the ciliary protein Rpgrip1l.
  9. Appearing and disappearing acts of cilia.
  10. The ERK activator, BCI, inhibits ciliogenesis and causes defects in motor behavior, ciliary gating, and cytoskeletal rearrangement.
  11. Primary cilia control cellular patterning of Meibomian glands during morphogenesis but not lipid composition.
  12. Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.
  13. Polycystic kidney disease 2-like 1 channel contributes to the bitter aftertaste perception of quinine.
  14. Rab8 and TNPO1 are ciliary transport adaptors for GTPase Arl13b by interacting with its RVEP motif-containing ciliary targeting sequence.
  15. The cilia mechanosensation debate gets (bio)physical.
  1. JAMA. 2023 Mar 17.
    What Is Autosomal Dominant Polycystic Kidney Disease?
    Ahsan Alam, Emilie Cornec-Le Gall, Ronald D Perrone.
      
    DOI:  https://doi.org/10.1001/jama.2023.2161
  2. J Obstet Gynaecol Res. 2023 Mar 12.
    Genetic autopsy and genetic counseling for a case of fatal oligohydramnios due to de novo 17q12 deletion syndrome.
    Kana Hiromoto, Naoya Morisada, Shinya Tairaku, Kandai Nozu, Kazumoto Iijima, Toru Funakoshi.
      We report here a fatal oligohydramnios case, which was suspected due to autosomal recessive polycystic kidney disease at first, but genetic analysis using chorionic tissue and umbilical cord after stillbirth led to the diagnosis of 17q12 deletion syndrome. Subsequent genetic analysis of the parents showed no 17q12 deletion. In this case, if the fetus had autosomal recessive polycystic kidney disease, the recurrence rate in the next pregnancy was suspected to be 25%, but since it was a de novo autosomal dominant disorder, the recurrence rate is extremely low. When a fetal dysmorphic abnormality is detected, a genetic autopsy not only helps to understand the cause but also provides information about the recurrence rate. This information is important for the next pregnancy. A genetic autopsy is useful in cases of fetal deaths or abortions resulting from fetal dysmorphic abnormalities.
    Keywords:  17q12 deletion syndrome; Potter sequence; genetic autopsy; genetic counseling; prenatal diagnosis
    DOI:  https://doi.org/10.1111/jog.15634
  3. J Cell Biol. 2023 Apr 03. pii: e201911062. [Epub ahead of print]222(4):
    Septin-mediated RhoA activation engages the exocyst complex to recruit the cilium transition zone.
    Darya Safavian, Moshe S Kim, Hong Xie, Maha El-Zeiry, Oliva Palander, Lu Dai, Richard F Collins, Carol Froese, Rachel Shannon, Koh-Ichi Nagata, William S Trimble.
      Septins are filamentous GTPases that play important but poorly characterized roles in ciliogenesis. Here, we show that SEPTIN9 regulates RhoA signaling at the base of cilia by binding and activating the RhoA guanine nucleotide exchange factor, ARHGEF18. GTP-RhoA is known to activate the membrane targeting exocyst complex, and suppression of SEPTIN9 causes disruption of ciliogenesis and mislocalization of an exocyst subunit, SEC8. Using basal body-targeted proteins, we show that upregulating RhoA signaling at the cilium can rescue ciliary defects and mislocalization of SEC8 caused by global SEPTIN9 depletion. Moreover, we demonstrate that the transition zone components, RPGRIP1L and TCTN2, fail to accumulate at the transition zone in cells lacking SEPTIN9 or depleted of the exocyst complex. Thus, SEPTIN9 regulates the recruitment of transition zone proteins on Golgi-derived vesicles by activating the exocyst via RhoA to allow the formation of primary cilia.
    DOI:  https://doi.org/10.1083/jcb.201911062
  4. Mayo Clin Proc. 2023 Mar 15. pii: S0025-6196(23)00011-3. [Epub ahead of print]
    Clinical Implementation of an Artificial Intelligence Algorithm for Magnetic Resonance-Derived Measurement of Total Kidney Volume.
    Theodora A Potretzke, Panagiotis Korfiatis, Daniel J Blezek, Marie E Edwards, Jason R Klug, Cole J Cook, Adriana V Gregory, Peter C Harris, Fouad T Chebib, Marie C Hogan, Vicente E Torres, Candice W Bolan, Kumaresan Sandrasegaran, Akira Kawashima, Jeremy D Collins, Naoki Takahashi, Robert P Hartman, Eric E Williamson, Bernard F King, Matthew R Callstrom, Bradley J Erickson, Timothy L Kline.
      OBJECTIVE: To evaluate the performance of an internally developed and previously validated artificial intelligence (AI) algorithm for magnetic resonance (MR)-derived total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) when implemented in clinical practice.PATIENTS AND METHODS: The study included adult patients with ADPKD seen by a nephrologist at our institution between November 2019 and January 2021 and undergoing an MR imaging examination as part of standard clinical care. Thirty-three nephrologists ordered MR imaging, requesting AI-based TKV calculation for 170 cases in these 161 unique patients. We tracked implementation and performance of the algorithm over 1 year. A radiologist and a radiology technologist reviewed all cases (N=170) for quality and accuracy. Manual editing of algorithm output occurred at radiology or radiology technologist discretion. Performance was assessed by comparing AI-based and manually edited segmentations via measures of similarity and dissimilarity to ensure expected performance. We analyzed ADPKD severity class assignment of algorithm-derived vs manually edited TKV to assess impact.
    RESULTS: Clinical implementation was successful. Artificial intelligence algorithm-based segmentation showed high levels of agreement and was noninferior to interobserver variability and other methods for determining TKV. Of manually edited cases (n=84), the AI-algorithm TKV output showed a small mean volume difference of -3.3%. Agreement for disease class between AI-based and manually edited segmentation was high (five cases differed).
    CONCLUSION: Performance of an AI algorithm in real-life clinical practice can be preserved if there is careful development and validation and if the implementation environment closely matches the development conditions.
    DOI:  https://doi.org/10.1016/j.mayocp.2022.12.019
  5. World J Urol. 2023 Mar 17.
    The impact of pre-transplantation nephrectomy on quality of life in patients with autosomal dominant polycystic kidney disease.
    Paul Geertsema, Ron T Gansevoort, Lisanne P J Brenkman, Shosha E I Dekker, Damia V P Eleveld, Johan W de Fijter, Anna M Leliveld, Maya Levy, Esther Meijer, Robert A Pol, Emmelien E M Schillern, Jan-Stephan F Sanders, Niek F Casteleijn.
      PURPOSE: In selected ADPKD patients, a nephrectomy is required in the work-up for a kidney transplantation. Because the impact of this procedure is unknown, we investigated the effect of pre-transplantation nephrectomy on quality of life in this group.METHODS: In this retrospective cohort study all ADPKD patients, ≥ 18 years, who received a kidney transplantation in 2 ADPKD expertise centers between January 2000 and January 2016, were asked to participate. Quality of life was assessed using three validated questionnaires on three time points. Nephrectomy was performed in preparation for transplantation.
    RESULTS: Two hundred seventy-six ADPKD patients (53 ± 9 years, 56.2% male) were included. 98 patients (35.5%) underwent native nephrectomy in preparation for transplantation, of which 43 underwent bilateral nephrectomy. Pre-transplantation, ADPKD-IS scores were worse in the nephrectomy group vs. no-nephrectomy group (physical: 2.9 vs. 2.3, p < 0.001; emotional: 2.0 vs. 1.8, p = 0.03; fatigue: 3.0 vs. 2.3, p = 0.01). Post-transplantation and post-nephrectomy, ADPKD-IS scores improved significantly in both groups, with a significantly higher improvement in the nephrectomy group. During follow-up, all scores were still better compared to pre-transplantation. Observed physical QoL (ADPKD-IS physical 1.3 vs. 1.7, p = 0.04; SF-36 physical 50.0 vs. 41.3, p = 0.03) was better post-transplantation after bilateral nephrectomy compared to unilateral nephrectomy. In retrospect, 19.7% of patients would have liked to undergo a nephrectomy, while the decision not to perform nephrectomy was made by the treating physician.
    CONCLUSION: This study shows that pre-transplantation nephrectomy improves quality of life in selected ADPKD patients. Bilateral nephrectomy may be preferred, although the risk of additional complications should be weighted.
    Keywords:  ADPKD; Kidney transplantation; Nephrectomy; Polycystic kidney disease; Quality of life
    DOI:  https://doi.org/10.1007/s00345-023-04349-4
  6. Nat Commun. 2023 Mar 17. 14(1): 1506
    Structural insight into the intraflagellar transport complex IFT-A and its assembly in the anterograde IFT train.
    Yuanyuan Ma, Jun He, Shaobai Li, Deqiang Yao, Chenhui Huang, Jian Wu, Ming Lei.
      Intraflagellar transport (IFT) trains, the polymers composed of two multi-subunit complexes, IFT-A and IFT-B, carry out bidirectional intracellular transport in cilia, vital for cilia biogenesis and signaling. IFT-A plays crucial roles in the ciliary import of membrane proteins and the retrograde cargo trafficking. However, the molecular architecture of IFT-A and the assembly mechanism of the IFT-A into the IFT trains in vivo remains elusive. Here, we report the cryo-electron microscopic structures of the IFT-A complex from protozoa Tetrahymena thermophila. We find that IFT-A complexes present two distinct, elongated and folded states. Remarkably, comparison with the in situ cryo-electron tomography structure of the anterograde IFT train unveils a series of adjustments of the flexible arms in apo IFT-A when incorporated into the anterograde train. Our results provide an atomic-resolution model for the IFT-A complex and valuable insights into the assembly mechanism of anterograde IFT trains.
    DOI:  https://doi.org/10.1038/s41467-023-37208-2
  7. Nephrol Dial Transplant. 2023 Mar 13. pii: gfad050. [Epub ahead of print]
    The association of urinary epidermal growth factors with ADPKD disease severity and progression.
    DIPAK Consortium
      BACKGROUND: The epidermal growth factor receptor (EGFR) pathway is involved in kidney tissue repair and growth. Preclinical interventional data and scarce human data have suggested a role for this pathway in the pathophysiology of Autosomal Dominant Polycystic Kidney Disease (ADPKD), while other data have suggested that its activation is causally linked to repair of damaged kidney tissue. We hypothesize that urinary EGFR ligands, as a reflection of EGFR activity, are associated with kidney function decline in ADPKD in the context of tissue repair following injury, and as the disease progresses as a sign of insufficient repair.METHODS: In the present study, we measured the EGFR ligands, EGF and heparin binding-EGF (HB-EGF), in 24-h urine samples of 301 ADPKD patients and 72 age- and sex matched living kidney donors to dissect the role of the EGFR pathway in ADPKD. During a median follow-up of 2.5 years, the association of urinary EGFR ligand excretion with annual change in estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) in ADPKD patients was analyzed using mixed-models methods and the expression of three closely related EGFR family receptors in ADPKD kidney tissue was investigated by immunohistochemistry. Additionally, the effect of reducing renal mass (after kidney donation), was assessed to investigate whether urinary EGF matches this reduction and thus reflects the amount of remaining healthy kidney tissue.
    RESULTS: At baseline, urinary HB-EGF did not differ between ADPKD patients and healthy controls (p = 0.6), whereas a lower urinary EGF excretion was observed in ADPKD patients (18.6 [11.8-27.8] compared to healthy controls (51.0 [34.9-65.4] µg/24 h, p < 0.001). Urinary EGF was positively associated with baseline eGFR (R = 0.54, p < 0.001) and a lower EGF was strongly associated with a more rapid GFR decline, even when adjusted for ADPKD severity markers (β = 1.96, p < 0.001), whereas HB-EGF was not. Expression of the EGFR, but not other EGFR-related receptors, was observed in renal cysts but was absent in non-ADPKD kidney tissue. Finally, unilateral nephrectomy resulted in a decrease of 46.4 [-63.3 to -17.6]% in urinary EGF excretion, alongside a decrease of 35.2 ± 7.2% in eGFR and 36.8 ± 6.9% in mGFR, whereas maximal mGFR (measured after dopamine induced hyperperfusion) decreased by 46.1 ± 7.8% (all p < 0.001).
    CONCLUSIONS: Our data suggest that lower urinary EGF excretion may be a valuable novel predictor for kidney function decline in patients with ADPKD.
    Keywords:  ADPKD; EGF; EGFR; kidney function; repair; tubular mass
    DOI:  https://doi.org/10.1093/ndt/gfad050
  8. iScience. 2023 Mar 17. 26(3): 106249
    Structure of the N-terminal coiled-coil domains of the ciliary protein Rpgrip1l.
    Ran He, Guanhao Chen, Zhiwei Li, Jianchao Li.
      Rpgrip1l is one of the key ciliary proteins located at the transition zone of the primary cilium, an important organelle for cells to sense the outer environment. Mutations in the RPGRIP1L gene are associated with various ciliopathies. Here, we focused on the N-terminal coiled-coil of Rpgrip1l. By comprehensive biochemical and structural characterizations, we demonstrated that the two predicted coiled-coil regions (CC12) located at Rpgrip1l N-terminus each can form a stable parallel dimer. We further showed that overexpression of Rpgrip1l CC12 in NIH/3T3 cells significantly shortened the length of primary cilia, and this effect depended on the dimer formation. In addition, we found that CC12 of the homolog protein Rpgrip1 in mouse and human were significantly different from Rpgrip1l. Finally, we confirmed that some disease-related mutations can alter the dimeric states of CC12 of Rpgrip1l or Rpgrip1, which might explain the pathogenic mechanisms.
    Keywords:  Cell biology; Molecular biology; Structural biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106249
  9. J Biosci. 2023 ;pii: 8. [Epub ahead of print]48
    Appearing and disappearing acts of cilia.
    Shashank Arora, Mausam Rana, Ananya Sachdev, Jacinta S D'Souza.
      The past few decades have seen a rise in research on vertebrate cilia and ciliopathy, with interesting collaborations between basic and clinical scientists. This work includes studies on ciliary architecture, composition, evolution, and organelle generation and its biological role. The human body has cells that harbour any of the following four types of cilia: 9+0 motile, 9+0 immotile, 9+2 motile, and 9+2 immotile. Depending on the type, cilia play an important role in cell/fluid movement, mating, sensory perception, and development. Defects in cilia are associated with a wide range of human diseases afflicting the brain, heart, kidneys, respiratory tract, and reproductive system. These are commonly known as ciliopathies and affect millions of people worldwide. Due to their complex genetic etiology, diagnosis and therapy have remained elusive. Although model organisms like Chlamydomonas reinhardtii have been a useful source for ciliary research, reports of a fascinating and rewarding translation of this research into mammalian systems, especially humans, are seen. The current review peeks into one of the complex features of this organelle, namely its birth, the common denominators across the formation of both 9+0 and 9+2 ciliary types, the molecules involved in ciliogenesis, and the steps that go towards regulating their assembly and disassembly.
  10. Life Sci Alliance. 2023 Jun;pii: e202301899. [Epub ahead of print]6(6):
    The ERK activator, BCI, inhibits ciliogenesis and causes defects in motor behavior, ciliary gating, and cytoskeletal rearrangement.
    Larissa L Dougherty, Soumita Dutta, Prachee Avasthi.
      MAPK pathways are well-known regulators of the cell cycle, but they have also been found to control ciliary length in a wide variety of organisms and cell types from Caenorhabditis elegans neurons to mammalian photoreceptors through unknown mechanisms. ERK1/2 is a MAP kinase in human cells that is predominantly phosphorylated by MEK1/2 and dephosphorylated by the phosphatase DUSP6. We have found that the ERK1/2 activator/DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), inhibits ciliary maintenance in Chlamydomonas and hTERT-RPE1 cells and assembly in Chlamydomonas These effects involve inhibition of total protein synthesis, microtubule organization, membrane trafficking, and KAP-GFP motor dynamics. Our data provide evidence for various avenues for BCI-induced ciliary shortening and impaired ciliogenesis that gives mechanistic insight into how MAP kinases can regulate ciliary length.
    DOI:  https://doi.org/10.26508/lsa.202301899
  11. Commun Biol. 2023 Mar 17. 6(1): 282
    Primary cilia control cellular patterning of Meibomian glands during morphogenesis but not lipid composition.
    Céline Portal, Yvonne Lin, Varuni Rastogi, Cornelia Peterson, Samuel Chi-Hung Yiu, James W Foster, Amber Wilkerson, Igor A Butovich, Carlo Iomini.
      Meibomian glands (MGs) are modified sebaceous glands producing the tear film's lipids. Despite their critical role in maintaining clear vision, the mechanisms underlying MG morphogenesis in development and disease remain obscure. Cilia-mediate signals are critical for the development of skin adnexa, including sebaceous glands. Thus, we investigated the role of cilia in MG morphogenesis during development. Most cells were ciliated during early MG development, followed by cilia disassembly during differentiation. In mature glands, ciliated cells were primarily restricted to the basal layer of the proximal gland central duct. Cilia ablation in keratine14-expressing tissue disrupted the accumulation of proliferative cells at the distal tip but did not affect the overall rate of proliferation or apoptosis. Moreover, impaired cellular patterning during elongation resulted in hypertrophy of mature MGs with increased meibum volume without altering its lipid composition. Thus, cilia signaling networks provide a new platform to design therapeutic treatments for MG dysfunction.
    DOI:  https://doi.org/10.1038/s42003-023-04632-5
  12. Elife. 2023 Mar 15. pii: e82395. [Epub ahead of print]12
    Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.
    Yuanyuan Li, Wenyan Xu, Svetlana Makova, Martina Brueckner, Zhaoxia Sun.
      Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently no targeted therapy is available for this disease. INVS/NPHP2 is one of the 25 NPHP genes identified to date. In mouse, global knockout of Invs leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type specific knockout mouse models of Invs, investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invsflox/flox;Foxd1-Cre mice, where Invs is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Invsflox/flox;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invsflox/flox;Cdh16-Cre mutant kidney, supporting a significant interaction of cilia and Invs function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in Invs mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.
    Keywords:  cell biology; developmental biology; mouse
    DOI:  https://doi.org/10.7554/eLife.82395
  13. Sci Rep. 2023 Mar 15. 13(1): 4271
    Polycystic kidney disease 2-like 1 channel contributes to the bitter aftertaste perception of quinine.
    Takahiro Shimizu, Takuto Fujii, Keisuke Hanita, Ryo Shinozaki, Yusaku Takamura, Yoshiro Suzuki, Teppei Kageyama, Mizuki Kato, Hisao Nishijo, Makoto Tominaga, Hideki Sakai.
      Bitterness is an important physiological function in the defense responses to avoid toxic foods. The taste receptor 2 family is well known to mediate bitter taste perception in Type II taste cells. Here, we report that the polycystic kidney disease 2-like 1 (PKD2L1) channel is a novel sensor for the bitter aftertaste in Type III taste cells. The PKD2L1 channel showed rebound activation after the washout of quinine, a bitter tastant, in electrophysiological whole-cell recordings of the PKD2L1-expressing HEK293T cells and Ca2+-imaging analysis of Type III taste cells isolated from wild-type PKD2L1 mice. In the short-term two-bottle preference and lick tests in vivo, the wild-type mice avoided normal water while the PKD2L1-knockout mice preferred normal water after they ingested the quinine-containing water. These results may explain the new mechanism of the quinine-triggered bitter aftertaste perception in Type III taste cells.
    DOI:  https://doi.org/10.1038/s41598-023-31322-3
  14. J Biol Chem. 2023 Mar 10. pii: S0021-9258(23)00246-6. [Epub ahead of print] 104604
    Rab8 and TNPO1 are ciliary transport adaptors for GTPase Arl13b by interacting with its RVEP motif-containing ciliary targeting sequence.
    Divyanshu Mahajan, Viswanadh Madugula, Lei Lu.
      Arl13b, an ARF/Arl-family GTPase, is highly enriched in the cilium. Recent studies have established Arl13b as one of the most crucial regulators for ciliary organization, trafficking, and signaling. The ciliary localization of Arl13b is known to require the RVEP motif. However, its cognitive ciliary transport adaptor has been elusive. Here, by imaging the ciliary localization of truncation and point mutations, we defined the ciliary targeting sequence (CTS) of Arl13b as a C-terminal stretch of 17 amino acids containing the RVEP motif. We found Rab8-GDP, but not Rab8-GTP, and TNPO1 simultaneously and directly bind to the CTS of Arl13b in pull-down assays using cell lysates or purified recombinant proteins. Furthermore, Rab8-GDP substantially enhances the interaction between TNPO1 and CTS. Additionally, we determined that the RVEP motif is an essential element as its mutation abolishes the interaction of the CTS with Rab8-GDP and TNPO1 in pull-down and TurboID-based proximity ligation assays. Finally, knockdown of endogenous Rab8 or TNPO1 decreases the ciliary localization of endogenous Arl13b. Therefore, our results suggest Rab8 and TNPO1 might function together as a ciliary transport adaptor for Arl13b by interacting with its RVEP-containing CTS.
    Keywords:  Arl13b; Cilium; Rab8; TNPO1; ciliary targeting sequence
    DOI:  https://doi.org/10.1016/j.jbc.2023.104604
  15. Nat Rev Nephrol. 2023 Mar 13.
    The cilia mechanosensation debate gets (bio)physical.
    Dagmar Wachten, Pleasantine Mill.
      
    DOI:  https://doi.org/10.1038/s41581-023-00701-4
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