Article
Multidisciplinary Sciences
Ran He, Guanhao Chen, Zhiwei Li, Jianchao Li
Summary: In this study, it was found that the N-terminal coil structure of Rpgrip1l is made up of two parallel dimers. Overexpression of these dimers significantly shortened the length of primary cilia, and this effect was dependent on the formation of dimers. It was also observed that the N-terminal structure of Rpgrip1 in mouse and human differed significantly from Rpgrip1l. Furthermore, disease-related mutations were found to alter the dimeric states of Rpgrip1l or Rpgrip1, possibly explaining the mechanisms behind the associated pathologies.
Article
Biochemistry & Molecular Biology
Francesco Chiuso, Rossella delle Donne, Giuliana Giamundo, Laura Rinaldi, Domenica Borzacchiello, Federica Moraca, Daniela Intartaglia, Rosa Iannucci, Emanuela Senatore, Luca Lignitto, Corrado Garbi, Paolo Conflitti, Bruno Catalanotti, Ivan Conte, Antonio Feliciello
Summary: Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, renal abnormalities, postaxial polydactyly, and developmental defects. The E3 ubiquitin ligase PJA2 has been identified as a regulator of the BBSome, an octameric complex that controls ciliary trafficking. Ubiquitylation of BBS1 by PJA2 stabilizes the BBSome and promotes its binding to BBS3, leading to proper ciliary membrane targeting. Disruption of PJA2 or expression of a ubiquitylation-defective BBS1 mutant affects GPCR trafficking and gene transcription, recapitulating the BBS phenotype in a medaka fish model.
Article
Genetics & Heredity
Jennifer Lennon, Petra zur Lage, Alex von Kriegsheim, Andrew P. Jarman
Summary: Axonemal dynein motors are complex protein complexes that drive ciliary movement. The Drosophila homologues of DNAAF4 and DNAAF6, CG14921/Dnaaf4 and CG5048/Dnaaf6, are found to associate in a complex similar to R2TP and play a crucial role in dynein assembly during the development of motile cilia.
FRONTIERS IN GENETICS
(2022)
Article
Cell Biology
Jonathon Howard, Alexander Chasteen, Xiaoyi Ouyang, Veikko F. Geyer, Pablo Sartori
Summary: Cilia and flagella are organelles that propel cells and drive fluid flow. The bending waves generated by dynein motor proteins play a crucial role in this process, but the exact location of these force-generating dyneins is still unclear. Researchers used a molecular-mechanics approach to predict the location of these dyneins and verified their predictions using cryogenic electron microscopy.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shichao Duan, Hao Li, Yirong Zhang, Suming Yang, Yawen Chen, Benhua Qiu, Cheng Huang, Juan Wang, Jinsong Li, Xueliang Zhu, Xiumin Yan
Summary: This study reveals the molecular switch function of small GTPase Rabl2 in the passage through the ciliary barrier transition zone, where GTP hydrolysis regulates the outward passage of BBSome and its cargos with retrograde IFT machinery crucial for proper ciliary signaling.
Article
Biochemistry & Molecular Biology
Karen Lange, Sunayna Best, Sofia Tsiropoulou, Ian Berry, Colin A. Johnson, Oliver E. Blacque
Summary: This study successfully used the C. elegans animal model to interpret missense VUS alleles of the TMEM67 gene through genome editing and quantitative functional assays, distinguishing between benign and pathogenic variants. The results were validated in human cell lines, demonstrating that C. elegans is a viable in vivo animal model for rapid and cost-effective interpretation of ciliopathy-associated missense VUS alleles.
HUMAN MOLECULAR GENETICS
(2021)
Review
Physiology
Kelly M. DeMars, Madeleine R. Ross, Alana Starr, Jeremy C. McIntyre
Summary: Neuronal primary cilia play a critical role in central regulation of energy homeostasis. These microtubule-based organelles serve as signaling antennae for metabolic status and impaired ciliary function can lead to obesity-related disorders. In addition to metabolic signaling, primary cilia also modulate catecholamine neuromodulation and shape neuronal circuitry. This review aims to highlight current research on the mechanisms of primary cilium-regulated metabolic drives for maintaining energy homeostasis.
FRONTIERS IN PHYSIOLOGY
(2023)
Review
Cell Biology
Julia Saez Conde, Samuel Dean
Summary: African trypanosomes, early branching protists causing trypanosomiasis, have been extensively studied for over a century and have contributed significantly to our understanding of eukaryotic biology. This article discusses the structural features of their flagellum and its role in transmission and virulence, highlighting the potential of targeting flagellar function for treating trypanosome infections and eradicating trypanosomiasis.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Biology
Petra Zur Lage, Zhiyan Xi, Jennifer Lennon, Iain Hunter, Wai Kit Chan, Alfonso Bolado Carrancio, Alex von Kriegsheim, Andrew P. Jarman
Summary: Ciliary motility in humans relies on highly conserved axoneme-specific dynein motor complexes, and mutations in these motors can lead to primary ciliary dyskinesia (PCD). Research in Drosophila has identified a less-known assembly factor, DNAAF3, which is essential for the function of mechanosensory neurons and sperm-producing cells in fruit flies. Mutations in DNAAF3 result in deaf larvae and uncoordinated adults, indicating a dysfunction in Ch neurons. Additionally, the absence of dynein arms in mutant Ch neuron cilia and immotile sperm with disrupted axoneme further demonstrates the importance of dynein motors in ciliary function and sperm motility.
Article
Cell Biology
Estefania Calvo-Alvarez, Serge Bonnefoy, Audrey Salles, Fiona E. Benson, Paul G. McKean, Philippe Bastin, Brice Rotureau
Summary: FLAM8 is not only a marker for flagellum length control in Trypanosoma brucei, but also reflects flagellum maturation in different parasite cycle stages, and even predicts daughter cell fate in specific tissue divisions.
CELLULAR MICROBIOLOGY
(2021)
Review
Microbiology
Scott M. Landfear
Summary: This review highlights recent advances in understanding the flagellar function in various biological contexts encountered by Leishmania parasites.
Article
Pharmacology & Pharmacy
Erasmia Rouka, Rajesh M. Jagirdar, Ioannis Sarrigeorgiou, Eleanna Pitaraki, Sotirios I. Sinis, Charalambos Varsamas, Eleftherios D. Papazoglou, Ourania S. Kotsiou, Peggy Lymberi, Anastasios Giannou, Chrissi Hatzoglou, Konstantinos I. Gourgoulianis, Sotirios G. Zarogiannis
Summary: This study reveals the importance of primary cilium in malignant pleural mesothelioma (MPM) and its relationship with the BBSome molecular complex. The differential expression of BBSome genes in different dimensions of cell culture suggests their potential as therapeutic targets for MPM.
PHARMACOLOGICAL REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Emanuela Senatore, Francesco Chiuso, Laura Rinaldi, Daniela Intartaglia, Rossella Delle Donne, Emilia Pedone, Bruno Catalanotti, Luciano Pirone, Bianca Fiorillo, Federica Moraca, Giuliana Giamundo, Giovanni Scala, Andrea Raffeiner, Omar Torres-Quesada, Eduard Stefan, Marcel Kwiatkowski, Alienke van Pijkeren, Manuela Morleo, Brunella Franco, Corrado Garbi, Ivan Conte, Antonio Feliciello
Summary: A novel complex assembled at centrosomes by TBC1D31, including praja2, PKA, and OFD1, is essential for ciliogenesis. PKA phosphorylates OFD1 at ser735 upon GPCR-cAMP stimulation, promoting OFD1 proteolysis through the praja2-UPS circuitry. Disruption of this control mechanism may lead to human genetic disorders.
Article
Cell Biology
Leah Schembs, Ariane Willems, Kerstin Hasenpusch-Theil, James D. Cooper, Katie Whiting, Karen Burr, Sunniva M. K. Bostrand, Bhuvaneish T. Selvaraj, Siddharthan Chandran, Thomas Theil
Summary: This study reveals the importance of primary cilia in dorsal and ventral patterning in human corticogenesis, identifies the tissue-specific role of the INPP5E gene as a negative regulator of SHH signaling, and suggests implications for the pathogenesis of neurodevelopmental disorders.
Article
Biochemistry & Molecular Biology
Niels Boegholm, Narcis A. Petriman, Marta Loureiro-Lopez, Jiaolong Wang, Miren Itxaso Santiago Vela, Beibei Liu, Tomoharu Kanie, Roy Ng, Peter K. Jackson, Jens S. Andersen, Esben Lorentzen
Summary: Cilia are important cellular organelles for signaling and motility and are constructed via intraflagellar transport (IFT). RabL2 localizes to the basal body of cilia via an interaction with CEP19 before downstream association with the IFT machinery. Reconstituted pentameric IFT complex containing IFT81/74 enhances the GTP hydrolysis rate of RabL2. Structural models of RabL2-containing IFT complexes validate the architectural understanding of RabL2 incorporation into the IFT complex.
Article
Biochemistry & Molecular Biology
Clare Halliday, Karen Billington, Ziyin Wang, Ross Madden, Samuel Dean, Jack Daniel Sunter, Richard John Wheeler
MOLECULAR AND BIOCHEMICAL PARASITOLOGY
(2019)
Article
Multidisciplinary Sciences
Jack D. Sunter, Ryuji Yanase, Ziyin Wang, Carolina Moura Costa Catta-Preta, Flavia Moreira-Leite, Jitka Myskova, Katerina Pruzinova, Petr Volf, Jeremy C. Mottram, Keith Gull
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Biology
Samuel Dean, Flavia Moreira-Leite, Keith Gull
Article
Biochemistry & Molecular Biology
Hana Vachova, Glenda Alquicer, Miroslava Sedinova, Jana Sachova, Miluse Hradilova, Vladimir Varga
MOLECULAR AND BIOCHEMICAL PARASITOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Petra Kiesel, Gonzalo Alvarez Viar, Nikolai Tsoy, Riccardo Maraspini, Peter Gorilak, Vladimir Varga, Alf Honigmann, Gaia Pigino
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2020)
Review
Pharmacology & Pharmacy
Samuel Dean
Summary: Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans and Nagana disease in cattle. These diseases are prevalent in sub-Saharan Africa and currently lack any effective vaccines or treatments.
CURRENT PHARMACEUTICAL DESIGN
(2021)
Article
Plant Sciences
Michael Hammond, Martin Zoltner, Jack Garrigan, Erin Butterfield, Vladimir Varga, Julius Lukes, Mark C. Field
Summary: Through proteomic analysis of the flagella of Euglena gracilis, unexpected similarities with mammalian flagella and a vast array of signal transduction components coordinating motility were identified. The significant adaptations within the flagellum of E. gracilis, linked to its highly flexible lifestyle, were also revealed.
Article
Biochemistry & Molecular Biology
Peter Gorilak, Martina Pruzincova, Hana Vachova, Marie Olsinova, Marketa Schmidt Cernohorska, Vladimir Varga
Summary: Expansion microscopy (ExM) is a powerful super-resolution method that faithfully reproduces cell morphology and complements electron microscopy approaches by providing more quantitative data. It can identify rare cell types in a population and visualize proteins tagged with small epitope tags, facilitating studies on cell structures.
Review
Cell Biology
Julia Saez Conde, Samuel Dean
Summary: African trypanosomes, early branching protists causing trypanosomiasis, have been extensively studied for over a century and have contributed significantly to our understanding of eukaryotic biology. This article discusses the structural features of their flagellum and its role in transmission and virulence, highlighting the potential of targeting flagellar function for treating trypanosome infections and eradicating trypanosomiasis.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Corinna Benz, Nora Muller, Sabine Kaltenbrunner, Hana Vachova, Marie Vancova, Julius Lukes, Vladimir Varga, Hassan Hashimi
Summary: In this study, a characterization of an orphaned X2 kinesin in Trypanosoma brucei was conducted. It was found that this kinesin interacts tightly with a likely inactive motor-like protein, TbPH1, and localizes to a poorly understood cytoskeletal structure called the microtubule quartet (MtQ). Another X2 kinesin, TbKifX2C, was also found to associate with the MtQ. Simultaneous ablation of TbKifX2A and TbPH1 resulted in morphological defects and an expansion of the flagellar pocket. This study provides insights into the co-evolution of the X2 kinesin family and the MtQ in trypanosomatids.
MOLECULAR MICROBIOLOGY
(2022)
Article
Microbiology
Lara Lopez-Escobar, Benjamin Hanisch, Clare Halliday, Midori Ishii, Bungo Akiyoshi, Samuel Dean, Jack Daniel Sunter, Richard John Wheeler, Keith Gull
Summary: ESB1, a specific protein found in the expression site body (ESB) of Trypanosoma brucei, is crucial for the activation of monoallelic VSG gene transcription and antigenic variation. It associates with DNA near the active VSG promoter and recruits RNA polymerase I, indicating its role as a transcription regulator.
NATURE MICROBIOLOGY
(2022)
Article
Cell Biology
Milad Jeilani, Karen Billington, Jack Daniel Sunter, Samuel Dean, Richard John Wheeler
Summary: By analyzing the protein localization properties of Trypanosome brucei, an early-branching eukaryote, this study reveals that nucleolar proteins in T. brucei share similar characteristics with those in common model eukaryotes, particularly basic amino acids. Experimental evidence showed that both homopolymer runs and distributed basic amino acids contribute to nucleolar targeting, along with a nuclear localization signal. These findings support the phase separation models of nucleolar formation and suggest a conserved mechanism for eukaryotic nucleolar targeting from the last eukaryotic common ancestor. Furthermore, the adaptation of physicochemical properties, such as an increase in basic residues, in cytoplasmic ribosome proteins may aid in their segregation.
JOURNAL OF CELL SCIENCE
(2022)
Editorial Material
Parasitology
Jack D. Sunter, Samuel Dean, Richard John Wheeler
Summary: TrypTag was a 4-year project to tag the N- and C-termini of almost all Trypanosoma brucei proteins with a fluorescent protein and record the subcellular localisation through images and manual annotation. We highlight the new routes to cell biological discovery this transformative resource is enabling for parasitologists and cell biologists.
TRENDS IN PARASITOLOGY
(2023)
Article
Microbiology
Karen Billington, Clare Halliday, Ross Madden, Philip Dyer, Amy Rachel Barker, Flavia Fernandes Moreira-Leite, Mark Carrington, Sue Vaughan, Christiane Hertz-Fowler, Samuel Dean, Jack Daniel Sunter, Richard John Wheeler, Keith Gull
Summary: Understanding the complex cell architecture and life cycle of Trypanosoma brucei, an important group of human, animal and plant unicellular parasites, is challenging due to a lack of knowledge about the functions of approximately 50% of its genome-encoded proteins. To address this, researchers developed TrypTag, a resource that maps the subcellular localization of 89% of the T. brucei proteome using fluorescence microscopy and cell lines expressing endogenously tagged proteins. TrypTag provides insights into function, defining lineage-specific organelle adaptations and allowing for the comprehensive analysis of eukaryotic flagella.
NATURE MICROBIOLOGY
(2023)
Article
Cell Biology
Madison Atkins, Jiri Tyc, Shahaan Shafiq, Manu Ahmed, Eloise Bertiaux, Artur Leonel De Castro Neto, Jack Sunter, Philippe Bastin, Samuel Dale Dean, Sue Vaughan
Summary: CEP164C contributes to the locking mechanism at the base of the flagellum in Trypanosoma brucei, with its localization to mature basal bodies of fully assembled old flagella. Inhibiting cytokinesis results in CEP164C acquisition on the new flagellum once it reaches the old flagellum length. These findings provide insight into the molecular mechanisms regulating flagella growth in maintaining existing while growing new flagella.
JOURNAL OF CELL BIOLOGY
(2021)