bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021‒11‒28
seventeen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Insights into the Regulation of Ciliary Disassembly.
  2. Feline Polycystic Kidney Disease: An Update.
  3. The Mitochondrial Ca2+ import complex is altered in ADPKD.
  4. Heterogeneity of cell composition and origin identified by single-cell transcriptomics in renal cysts of patients with autosomal dominant polycystic kidney disease.
  5. Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease.
  6. Metformin Improves Relevant Disease Parameters in an Autosomal Dominant Polycystic Kidney Disease Mouse Model.
  7. The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis.
  8. Limited Performance of Estimated Total Kidney Volume for Follow-up of ADPKD.
  9. LUBAC regulates ciliogenesis by promoting CP110 removal from the mother centriole.
  10. Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease.
  11. Reactivities of a Prostanoid EP2 Agonist, Omidenepag, Are Useful for Distinguishing between 3D Spheroids of Human Orbital Fibroblasts without or with Graves' Orbitopathy.
  12. Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease.
  13. The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and Cilia to Regulate Ciliogenesis and Ciliary Protein Traffic.
  14. Cancer-associated fibroblasts as cellular vehicles in endometrial cancer cell migration.
  15. Role and mechanism of intraflagellar transport in mammalian spermiogenesis.
  16. Gβγ mediates activation of Rho guanine nucleotide exchange factor ARHGEF17 which promotes metastatic lung cancer progression.
  17. Giant obscurin regulates migration and metastasis via RhoA-dependent cytoskeletal remodeling in pancreatic cancer.
  1. Cells. 2021 Nov 01. pii: 2977. [Epub ahead of print]10(11):
    Insights into the Regulation of Ciliary Disassembly.
    Maulin M Patel, Leonidas Tsiokas.
      The primary cilium, an antenna-like structure that protrudes out from the cell surface, is present in most cell types. It is a microtubule-based organelle that serves as a mega-signaling center and is important for sensing biochemical and mechanical signals to carry out various cellular processes such as proliferation, migration, differentiation, and many others. At any given time, cilia length is determined by a dynamic balance of cilia assembly and disassembly processes. Abnormally short or long cilia can cause a plethora of human diseases commonly referred to as ciliopathies, including, but not limited to, skeletal malformations, obesity, autosomal dominant polycystic kidney disease, retinal degeneration, and bardet-biedl syndrome. While the process of cilia assembly is studied extensively, the process of cilia disassembly and its biological role(s) are less well understood. This review discusses current knowledge on ciliary disassembly and how different cellular processes and molecular signals converge to carry out this process. This information will help us understand how the process of ciliary disassembly is regulated, identify the key steps that need further investigation, and possibly design therapeutic targets for a subset of ciliopathies that are causally linked to defective ciliary disassembly.
    Keywords:  cilia; cilia disassembly; ciliopathies
    DOI:  https://doi.org/10.3390/cells10112977
  2. Vet Sci. 2021 Nov 08. pii: 269. [Epub ahead of print]8(11):
    Feline Polycystic Kidney Disease: An Update.
    Lorie Schirrer, Pablo Jesús Marín-García, Lola Llobat.
      Polycystic kidney disease (PKD) is a disease that affects felines and other mammals, such as humans. The common name is autosomal dominant polycystic kidney disease (ADPKD) and causes a progressive development of fluid-filled cysts in the kidney and sometimes in other organs as the liver and pancreas. The formation and growth of cysts progress slowly, causing deterioration of kidney tissue and a gradual decrease in kidney function, leading to irreversible kidney failure. Feline PKD or ADPKD in humans are hereditary pathologies of autosomal dominant transmission. ADPKD is one of the genetic diseases with the highest prevalence in humans. In cats, this disease also has a high prevalence, mainly in the Persian breed, being one of the most common feline genetic diseases. Imaging tests seem to be the most reliable method for diagnosis of the disease, although more genetic tests are being developed to detect the presence of the responsible mutation. In this review, we summarize the current knowledge about feline PKD to guide future research related to an adequate diagnosis and early detection of causal mutations. It can allow the establishment of selection programs to reduce or eliminate this pathology in feline breeds.
    Keywords:  cat; control disease; feline polycystic kidney disease; hereditary pathology
    DOI:  https://doi.org/10.3390/vetsci8110269
  3. Cell Calcium. 2021 Nov 19. pii: S0143-4160(21)00155-X. [Epub ahead of print]101 102501
    The Mitochondrial Ca2+ import complex is altered in ADPKD.
    Murali K Yanda, Vartika Tomar, Robert Cole, William B Guggino, Liudmila Cebotaru.
      Mutations in either of the polycystic kidney disease genes, PKD1 or PKD2, engender the growth of cysts, altering renal function. Cystic growth is supported by major changes in cellular metabolism, some of which involve the mitochondrion, a major storage site for Ca2+ and a key organelle in cellular Ca2+ signaling. The goal here was to understand the role of components of the mitochondrial Ca2+ uptake complex in PC1-mutant cells in autosomal dominant polycystic kidney disease (ADPKD). We found that the mitochondrial Ca2+ uniporter (MCU) and voltage-dependent anion channels 1& 3 (VDAC) were down-regulated in different mouse and cell models of ADPKD along with the Ca2+-dependent enzyme, pyruvate dehydrogenase phosphatase (PDHX). The release of Ca2+ from the endoplasmic reticulum, and Ca2+ uptake by the mitochondria were upregulated in PC1(polycystin)-null cells. We also observed an enhanced staining with MitoTracker Red CMXRos in PC1-null cultured cells than in PC1-containing cells and a substantially higher increase in response to ER Ca2+ release. Increased colocalization of the Ca2+ sensitive dye, rhodamine2, with MitoTracker Green suggested an increase Ca2+ entry into the mitochondria in PC1 null cells subsequent to Ca2+ release from the ER or from Ca2+ entry from the extracellular solution. These data clearly demonstrate abnormal release of Ca2+ by the ER and corresponding alterations in Ca2+ uptake by the mitochondria in PC1-null cells. Importantly, inhibiting mitochondrial Ca2+ uptake with the specific inhibitor Ru360 inhibited cyst growth and altered both apoptosis and cell proliferation. We further show that the decrease in mitochondrial proteins and abnormally high Ca2+ signaling can be reversed by application of the cystic fibrosis (CFTR) corrector, VX-809. We conclude that enhanced Ca2+ signaling and alterations in proteins association with the mitochondrial Ca2+ uptake complex are associated with malfunction of PC1. Finally, our results identify novel therapeutic targets for treating ADPKD.
    Keywords:  Adult onset polycystic kidney disease; CFTR modulators; Calcium; Mitochondria
    DOI:  https://doi.org/10.1016/j.ceca.2021.102501
  4. Theranostics. 2021 ;11(20): 10064-10073
    Heterogeneity of cell composition and origin identified by single-cell transcriptomics in renal cysts of patients with autosomal dominant polycystic kidney disease.
    Qiong Li, Yuchen Wang, Wenfeng Deng, Yanna Liu, Jian Geng, Ziyan Yan, Fei Li, Binshen Chen, Zhuolin Li, Renfei Xia, Wenli Zeng, Rumin Liu, Jian Xu, Fu Xiong, Chin-Lee Wu, Yun Miao.
      Rationale: Renal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD) can originate from any nephron segments, including proximal tubules (PT), the loop of Henle (LOH), distal tubules (DT), and collecting ducts (CD). Previous studies mostly used limited cell markers and failed to identify cells negative for these markers. Therefore, the cell composition and origin of ADPKD cyst are still unclear, and mechanisms of cystogenesis of different origins await further exploration. Methods: We performed single-cell RNA sequencing for the normal kidney tissue and seven cysts derived from superficial or deep layers of the polycystic kidney from an ADPKD patient. Results: Twelve cell types were identified and analyzed. We found that a renal cyst could be derived either from CD or both PT and LOH. Gene set variation analysis (GSVA) showed that epithelial mesenchymal transition (EMT), TNFA signaling via the NFKB pathways, and xenobiotic metabolism were significantly activated in PT-derived cyst epithelial cells while robust expression of genes involved in G2M Checkpoint, mTORC1 signaling, E2F Targets, MYC Targets V1, MYC Targets V2 were observed in CD-derived cells. Conclusion: Our results revealed that a single cyst could originate from CD or both PT and LOH, suggesting heterogeneity of polycystic composition and origin. Furthermore, cyst epithelial cells with different origins have different gene set activation.
    Keywords:  ADPKD; Heterogeneity; Single-cell transcriptomics
    DOI:  https://doi.org/10.7150/thno.57220
  5. Cells. 2021 Nov 17. pii: 3204. [Epub ahead of print]10(11):
    Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease.
    Bo Ning, Chuanzhi Guo, Anqi Kong, Kongdong Li, Yimin Xie, Haifeng Shi, Jie Gu.
      The kidney is an important organ for the maintenance of Ca2+ homeostasis in the body. However, disruption of Ca2+ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy. During the progression of kidney disease, Ca2+ signaling plays key roles in various cell activities such as necrosis, apoptosis, eryptosis and autophagy. Importantly, there are complex Ca2+ flux networks between the endoplasmic reticulum (ER), mitochondria and lysosomes which regulate intracellular Ca2+ signaling in renal cells and contribute to kidney disease. In addition, Ca2+ signaling also links the crosstalk between various cell deaths and autophagy under the stress of heavy metals or high glucose. In this regard, we present a review of Ca2+ signaling in cell death and crosstalk with autophagy and its potential as a therapeutic target for the development of new and efficient drugs against kidney diseases.
    Keywords:  Ca2+ signaling; autophagy; cell death; kidney diseases
    DOI:  https://doi.org/10.3390/cells10113204
  6. Am J Physiol Renal Physiol. 2021 Nov 22.
    Metformin Improves Relevant Disease Parameters in an Autosomal Dominant Polycystic Kidney Disease Mouse Model.
    Nuria M Pastor-Soler, Hui Li, Jessica Pham, Daniel Rivera, Pei-Yin Ho, Valeria Mancino, Biagio Saitta, Kenneth R Hallows.
      Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 genes encoding polycystins, presents with progressive development of kidney cysts and eventual end-stage kidney disease (ESKD) with limited treatment options. Previous work showed that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of CFTR-mediated fluid secretion, mTOR, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knock-in point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have slow progression to ESKD, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 months of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype than males. Metformin treatment reduced the ratio of total kidney weight to body weight relative to age- and sex-matched untreated controls at both 9 and 12 months and reduced cystic index in females at 9 months. Metformin also increased glomerular filtration rate (GFR), lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 vs. untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.
    Keywords:  ADPKD; AMPK; GFR; kidney; metformin
    DOI:  https://doi.org/10.1152/ajprenal.00298.2021
  7. Int J Mol Sci. 2021 Nov 12. pii: 12253. [Epub ahead of print]22(22):
    The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis.
    Fatma Mansour, Felix J Boivin, Iman B Shaheed, Markus Schueler, Kai M Schmidt-Ott.
      The primary cilium is found in most mammalian cells and plays a functional role in tissue homeostasis and organ development by modulating key signaling pathways. Ciliopathies are a group of genetically heterogeneous disorders resulting from defects in cilia development and function. Patients with ciliopathic disorders exhibit a range of phenotypes that include nephronophthisis (NPHP), a progressive tubulointerstitial kidney disease that commonly results in end-stage renal disease (ESRD). In recent years, distal appendages (DAPs), which radially project from the distal end of the mother centriole, have been shown to play a vital role in primary ciliary vesicle docking and the initiation of ciliogenesis. Mutations in the genes encoding these proteins can result in either a complete loss of the primary cilium, abnormal ciliary formation, or defective ciliary signaling. DAPs deficiency in humans or mice commonly results in NPHP. In this review, we outline recent advances in our understanding of the molecular functions of DAPs and how they participate in nephronophthisis development.
    Keywords:  centrosome; ciliogenesis; distal appendages; nephronophthisis; transition fibers
    DOI:  https://doi.org/10.3390/ijms222212253
  8. Kidney Int Rep. 2021 Nov;6(11): 2821-2829
    Limited Performance of Estimated Total Kidney Volume for Follow-up of ADPKD.
    Nathalie Demoulin, Victoria Nicola, Nicolas Michoux, Valentine Gillion, Thien Anh Ho, Caroline Clerckx, Yves Pirson, Laurence Annet.
      Introduction: Total kidney volume (TKV) is a qualified biomarker for disease progression in autosomal dominant polycystic kidney disease (ADPKD). Recent studies suggest that TKV estimated using ellipsoid formula correlates well with TKV measured by manual planimetry (gold standard). We investigated whether the ellipsoid formula could replace manual planimetry for follow-up of ADPKD patients.Methods: Abdominal magnetic resonance images of patients with ADPKD performed between January 1, 2013, and June 31, 2019, in Saint-Luc Hospital, Brussels, were used. Two radiologists independently performed manual TKV (mTKV) measures and kidney axial measures necessary for estimating TKV (eTKV) using ellipsoid equation. Repeatability and reproducibility of axial measures, mTKV and eTKV, and agreement between mTKV and eTKV were assessed (Bland-Altman). Intraclass correlation coefficient (ICC) was used to assess agreement on Mayo Clinic Imaging Classification (MCIC) scores.
    Results: 140 patients were included with mean age 45±13 years, estimated glomerular filtration rate (eGFR) 71±31 ml/min per 1.73 m2, and mTKV 1697±1538 ml. Repeatability and reproducibility were superior for mTKV versus eTKV (repeatability coefficient 2.4% vs. 14% in senior reader, and reproducibility coefficient 6.7% vs. 15%). Intertechnique reproducibility coefficient (95% confidence interval [CI]) was 19% (17%, 21%) in senior reader. Intertechnique agreement on derived MCIC scores was very good (ICC = 0.924 [0.884, 0.949]).
    Conclusion: TKV estimated using ellipsoid equation demonstrates poor repeatability and reproducibility compared with that of mTKV. Intertechnique agreement is also limited, even when measurements are performed by an experienced radiologist. Estimated TKV, however, accurately determines MCIC score.
    Keywords:  ADPKD; TKV; ellipsoid equation; manual planimetry
    DOI:  https://doi.org/10.1016/j.ekir.2021.08.013
  9. J Cell Biol. 2022 Jan 03. pii: e202105092. [Epub ahead of print]221(1):
    LUBAC regulates ciliogenesis by promoting CP110 removal from the mother centriole.
    Xiao-Lin Shen, Jin-Feng Yuan, Xuan-He Qin, Guang-Ping Song, Huai-Bin Hu, Hai-Qing Tu, Zeng-Qing Song, Pei-Yao Li, Yu-Ling Xu, Sen Li, Xiao-Xiao Jian, Jia-Ning Li, Chun-Yu He, Xi-Ping Yu, Li-Yun Liang, Min Wu, Qiu-Ying Han, Kai Wang, Ai-Ling Li, Tao Zhou, Yu-Cheng Zhang, Na Wang, Hui-Yan Li.
      Primary cilia transduce diverse signals in embryonic development and adult tissues. Defective ciliogenesis results in a series of human disorders collectively known as ciliopathies. The CP110-CEP97 complex removal from the mother centriole is an early critical step for ciliogenesis, but the underlying mechanism for this step remains largely obscure. Here, we reveal that the linear ubiquitin chain assembly complex (LUBAC) plays an essential role in ciliogenesis by targeting the CP110-CEP97 complex. LUBAC specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole in ciliogenesis. We further identify that a pre-mRNA splicing factor, PRPF8, at the distal end of the mother centriole acts as the receptor of the linear ubiquitin chains to facilitate CP110 removal at the initial stage of ciliogenesis. Thus, our study reveals a direct mechanism of regulating CP110 removal in ciliogenesis and implicates the E3 ligase LUBAC as a potential therapy target of cilia-associated diseases, including ciliopathies and cancers.
    DOI:  https://doi.org/10.1083/jcb.202105092
  10. J Cardiovasc Dev Dis. 2021 Oct 29. pii: 144. [Epub ahead of print]8(11):
    Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease.
    Priyanka S Sagar, Sayanthooran Saravanabavan, Alexandra Munt, Annette T Y Wong, Gopala K Rangan.
      Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.2 μg/kg i.p. 5 days/week) or vehicle from postnatal weeks 3 to 10 did not alter kidney enlargement. To evaluate the efficacy in established disease, LPK rats received either PC (0.8 μg/kg i.p; 3 days/week), vehicle, E (50 mg/L in water) or the combination of PC + E from weeks 10 to 20. In established disease, PC also did not alter the progression of kidney enlargement, kidney cyst growth or decline in renal function in LPK rats. Moreover, the higher dose of PC was associated with increased serum calcium and weight loss. However, in established disease, the combination of PC + E reduced systolic blood pressure and heart-body weight ratio compared to vehicle and E alone (p < 0.05). In conclusion, the combination of PC + E attenuated cardiovascular disease but caused hypercalcaemia and did not alter kidney cyst growth in LPK rats.
    Keywords:  paricalcitol; polycystic kidney disease; vitamin D receptor agonists
    DOI:  https://doi.org/10.3390/jcdd8110144
  11. Cells. 2021 Nov 16. pii: 3196. [Epub ahead of print]10(11):
    Reactivities of a Prostanoid EP2 Agonist, Omidenepag, Are Useful for Distinguishing between 3D Spheroids of Human Orbital Fibroblasts without or with Graves' Orbitopathy.
    Yosuke Ida, Hanae Ichioka, Masato Furuhashi, Fumihito Hikage, Megumi Watanabe, Araya Umetsu, Hiroshi Ohguro.
      BACKGROUND: To obtain new insights into the activation of the thyroid-stimulating hormone (TSH) and insulin-like growth factor 1 (IGF-1) receptors in human orbital fibroblasts (n-HOFs), the effects of the prostanoid EP2 agonist, omidenepag (OMD), and a rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, ripasudil (Rip) were evaluated using three-dimension (3D) n-HOFs spheroids in the absence and presence of the recombinant human TSH receptor antibodies, M22 and IGF-1.METHODS: The effects of 100 nM OMD or 10 μM Rip on the physical properties, size, stiffness, and mRNA expression of several extracellular matrix (ECM) molecules, their regulator, inflammatory cytokines, and endoplasmic reticulum (ER) stress-related factors were examined and compared among 3D spheroids of n-HOFs, M22-/IGF-1-activated n-HOFs and GO-related human orbital fibroblasts (GHOFs).
    RESULTS: The physical properties and mRNA expressions of several genes of the 3D n-HOFs spheroids were significantly and diversely modulated by the presence of OMD or Rip. The OMD-induced effects on M22-/IGF-1-activated n-HOFs were similar to the effects caused by GHOHs, but quite different from those of n-HOFs.
    CONCLUSIONS: The findings presented herein indicate that the changes induced by OMD may be useful in distinguishing between n-HOFs and GHOFs.
    Keywords:  Graves’ orbitopathy; IGF-1; ROCK inhibitor; orbital fibroblast; prostanoid EP2 agonist; three-dimension (3D) cell culture
    DOI:  https://doi.org/10.3390/cells10113196
  12. Genes (Basel). 2021 Nov 05. pii: 1762. [Epub ahead of print]12(11):
    Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease.
    Shabarni Gupta, Justyna E Ozimek-Kulik, Jacqueline Kathleen Phillips.
      The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients.
    Keywords:  chronic kidney disease; cilia; cyst; intraflagellar transport; kidney; nephrocystin; nephronophthisis; polycystic kidney disease; polycystin
    DOI:  https://doi.org/10.3390/genes12111762
  13. Mol Biol Cell. 2021 Nov 24. mbcE21090443
    The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and Cilia to Regulate Ciliogenesis and Ciliary Protein Traffic.
    Rachel E Turn, Yihan Hu, Skylar I Dewees, Narra Devi, Michael P East, Katherine R Hardin, Tala Khatib, Joshua Linnert, Uwe Wolfrum, Michael J Lim, James E Casanova, Tamara Caspary, Richard A Kahn.
      ELMODs are a family of three mammalian paralogs that display GTPase activating protein (GAP) activity towards a uniquely broad array of ADP-ribosylation factor (ARF) family GTPases that includes ARF-like (ARL) proteins. ELMODs are ubiquitously expressed in mammalian tissues, highly conserved across eukaryotes, and ancient in origin, being present in the last eukaryotic common ancestor. We described functions of ELMOD2 in immortalized mouse embryonic fibroblasts (MEFs) in the regulation of cell division, microtubules, ciliogenesis, and mitochondrial fusion. Here, using similar strategies with the paralogs ELMOD1 and ELMOD3, we identify novel functions and locations of these cell regulators and compare them to those of ELMOD2, allowing determination of functional redundancy among the family members. We found strong similarities in phenotypes resulting from deletion of either Elmod1 or Elmod3 and marked differences from those arising in Elmod2 deletion lines. Deletion of either Elmod1 or Elmod3 results in the decreased ability of cells to form primary cilia, loss of a subset of proteins from cilia, and accumulation of some ciliary proteins at the Golgi, predicted to result from compromised traffic from the Golgi to cilia. These phenotypes are reversed upon activating mutant expression of either ARL3 or ARL16, linking their roles to ELMOD1/3 actions.
    DOI:  https://doi.org/10.1091/mbc.E21-09-0443
  14. Oncol Lett. 2022 Jan;23(1): 3
    Cancer-associated fibroblasts as cellular vehicles in endometrial cancer cell migration.
    Yap Chee Voon, Intan Sofia Omar, Ming-Heng Wu, Nur Akmarina B M Said, Ivy Chung.
      Cell motility is a critical step in the metastasis cascade. However, the role of cancer-associated fibroblasts (CAFs) in facilitating endometrial cancer (EC) cell motility remains unclear. The present study aimed to investigate the role of CAFs in EC motility in a 3D environment. A co-culture model was established using an EC cell line (ECC-1) and CAFs on a Matrigel® matrix and compared to the respective individual monocultures. It was demonstrated that endometrial CAFs increased the motility of the EC cell line, compared with the monoculture. Using live cell imaging, CAFs were observed to form cell projections that served as contact guidance for ECC-1 cell locomotion in the spheroid formation process. These effects were specific to CAFs, as fibroblasts isolated from benign endometrial tissue samples did not form cell projections. Molecular analysis revealed that RhoA/Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) signaling activation partly contributed to CAF-mediated ECC-1 cell migration. The presence of Matrigel® increased the mRNA expression of RhoA, and the mRNA and protein expression levels of its downstream effectors, ROCK1 and p-MLC, respectively, in the ECC-1 and CAF co-culture, as well as the ECC-1 and CAF monocultures. Interestingly, high phosphorylation levels of myosin light chain mediated the activation of RhoA/ROCK1 signaling in the ECC-1 and CAF co-culture. The ROCK1 inhibitor Y-27632 attenuated the motility of tumor cells in ECC-1 and CAF co-cultures. However, similar treatment led to a significant inhibition in the motility of the CAF monoculture, but not the ECC-1 monoculture. Moreover, tumor spheroid formation was inhibited due to a reduction in stress fiber formation in ECC-1 and CAF co-cultures. Altogether, these findings suggest that the regulation of the RhoA/ROCK1 signaling pathway is required for CAFs to serve as cellular vehicles in order for EC cells to migrate and form spheroids in a 3D environment.
    Keywords:  Rho family of GTPases; cancer-associated fibroblast; motility; tumor microenvironment; uterine cancer
    DOI:  https://doi.org/10.3892/ol.2021.13121
  15. Yi Chuan. 2021 Nov 20. 43(11): 1038-1049
    Role and mechanism of intraflagellar transport in mammalian spermiogenesis.
    Ting-Ting Ge, Lu Yuan, Wen-Hua Xu, Ying Zheng.
      Eukaryotic cilia and flagella are evolutionarily conserved organelles that protrude from the cell surface. The unique location and properties of cilia allow them to function in vital processes such as motility and signaling. Ciliary assembly and maintenance rely on intraflagellar transport (IFT). Bidirectional movement of IFT particles composed of IFT-A and IFT-B complexes is powered by kinesin-2 and dynein-2 motors. IFT delivers building blocks between their site of synthesis in the cell body and the ciliary assembly site at the tip of the cilium. The integrity of the flagellum, a specialized organelle of mammalian sperm to generate the motility, is critical for normal sperm function. Recent findings suggest that IFT is indispensable for sperm flagellum formation and male fertility in mice and human. In this review, we summarize the role and mechanisms of IFT proteins during enflagellation in spermiogenesis, thereby discussing the pathological mechanisms of male infertility and providing theoretical basis for the diagnosis and treatment of male infertility.
    Keywords:  intraflagellar transport; male infertility; spermiogenesis
    DOI:  https://doi.org/10.16288/j.yczz.21-206
  16. J Biol Chem. 2021 Nov 19. pii: S0021-9258(21)01249-7. [Epub ahead of print] 101440
    Gβγ mediates activation of Rho guanine nucleotide exchange factor ARHGEF17 which promotes metastatic lung cancer progression.
    Irving García-Jiménez, Rodolfo Daniel Cervantes-Villagrana, Jorge Eduardo Del-Río-Robles, Alejandro Castillo Kauil, Yarely Mabell Beltrán-Navarro, Jonathan García-Román, Guadalupe Reyes-Cruz, José Vázquez-Prado.
      Metastatic lung cancer is a major cause of death worldwide. Dissemination of cancer cells can be facilitated by various agonists within the tumor microenvironment, including by lysophosphatidic acid (LPA). We postulate that Rho guanine exchange factors (RhoGEFs), which integrate signaling cues driving cell migration, are critical effectors in metastatic cancer. Specifically, we addressed the hypothetical role of ARHGEF17, a RhoGEF, as a potential effector of Gβγ in metastatic lung cancer cells responding to LPA. Here, we show that ARHGEF17, originally identified as a tumor endothelial marker, is involved in tumor growth and metastatic dissemination of lung cancer cells in an immunocompetent murine model. Gene expression-based analysis of lung cancer datasets showed that increased levels of ARHGEF17 correlated with reduced survival of patients with advanced-stage tumors. Cellular assays also revealed that this RhoGEF participates in the invasive and migratory responses elicited by Gi protein-coupled LPA receptors via the Gβγ subunit complex. We demonstrate that this signaling heterodimer promoted ARHGEF17 recruitment to the cell periphery and to actin fibers. Moreover, Gβγ allosterically activates ARHGEF17 by the removal of inhibitory intramolecular restrictions. Taken together, our results indicate ARHGEF17 may be a valid potential target in the treatment of metastatic lung cancer.
    Keywords:  ARHGEF17; Gbetagamma; Rho guanine nucleotide exchange factor (RhoGEF); RhoA; actin cytoskeleton; cell migration; heterotrimeric G protein; lysophosphatidic acid; signal transduction
    DOI:  https://doi.org/10.1016/j.jbc.2021.101440
  17. Cancer Lett. 2021 Nov 23. pii: S0304-3835(21)00583-8. [Epub ahead of print]
    Giant obscurin regulates migration and metastasis via RhoA-dependent cytoskeletal remodeling in pancreatic cancer.
    Soontorn Tuntithavornwat, Daniel J Shea, Bin Sheng Wong, Talia Guardia, Se Jong Lee, Christopher L Yankaskas, Lei Zheng, Aikaterini Kontrogianni-Konstantopoulos, Konstantinos Konstantopoulos.
      Obscurins, encoded by the OBSCN gene, are giant cytoskeletal proteins with structural and regulatory roles. Large scale omics analyses reveal that OBSCN is highly mutated across different types of cancer, exhibiting a 5-8% mutation frequency in pancreatic cancer. Yet, the functional role of OBSCN in pancreatic cancer progression and metastasis has to be delineated. We herein show that giant obscurins are highly expressed in normal pancreatic tissues, but their levels are markedly reduced in pancreatic ductal adenocarcinomas. Silencing of giant obscurins in non-tumorigenic Human Pancreatic Ductal Epithelial (HPDE) cells and obscurin-expressing Panc5.04 pancreatic cancer cells induces an elongated, spindle-like morphology and faster cell migration via cytoskeletal remodeling. Specifically, depletion of giant obscurins downregulates RhoA activity, which in turn results in reduced focal adhesion density, increased microtubule growth rate and faster actin dynamics. Although OBSCN knockdown is not sufficient to induce de novo tumorigenesis, it potentiates tumor growth in a subcutaneous implantation model and exacerbates metastasis in a hemispleen murine model of pancreatic cancer metastasis, thereby shortening survival. Collectively, these findings reveal a critical role of giant obscurins as tumor suppressors in normal pancreatic epithelium whose loss of function induces RhoA-dependent cytoskeletal remodeling, and promotes cell migration, tumor growth and metastasis.
    Keywords:  Cytoskeleton; Metastasis; Migration
    DOI:  https://doi.org/10.1016/j.canlet.2021.11.016
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