cilium

The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor cilium. Despite advances in the understanding of retinal ciliopathies utilising animal disease models, they can often lack the ability to accurately mimic the observed patient phenotype, possibly due to structural and functional deviations from the human retina...

The primary cilium, a 1-3 μm long hair-like structure protruding from the surface of almost all cells in the vertebrate body, is critical for neuronal development and also functions in the adult. As the migratory neural crest settles into dorsal root ganglia (DRG) sensory neurons elaborate a single primary cilium at their soma that is maintained into adult stages. While it is not known if primary cilia are expressed in nociceptors, or their potential function in the mature DRG neuron, recent studies have shown a role for Hedgehog, whose signaling demonstrates a dependence on primary cilia, in nociceptor sensitization...

The Commander complex, a 16-protein assembly, plays multiple roles in cell homeostasis, cell cycle and immune response. It consists of copper-metabolism Murr1 domain proteins (COMMD1-10), coiled-coil domain-containing proteins (CCDC22 and CCDC93), DENND10 and the Retriever subcomplex (VPS26C, VPS29 and VPS35L), all expressed ubiquitously in the body and linked to various diseases. Here, we report the structure and key interactions of the endogenous human Commander complex by cryogenic-electron microscopy and mass spectrometry-based proteomics...

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive multisystem disease. The pathophysiological origin is a dysfunction of the primary cilium. Clinical symptoms are heterogeneous and variable: retinal dystrophy, obesity, polydactyly, kidney abnormalities, hypogenitalism and developmental delays are the most common features. By the approval of the melanocortin 4 receptor agonist setmelanotide, a drug therapy for BBS-associated hyperphagia and obesity can be offered for the first time. Hyperphagia and severe obesity represent a considerable burden and are associated with comorbidity and increased mortality risk...

ARL3 is essential for cilia development, and mutations in ARL3 are closely associated with ciliopathies. In a previous study, we observed distinct phenotypes of retinal dystrophy in patients with heterozygous ARL3T31A and compound heterozygous ARL3T31A/C118F mutations, indicating that different mutation types may exert diverse effects on their functions. Here, we generated transformed immortal fibroblast cells from patients carrying heterozygous ARL3T31A and compound heterozygous ARL3T31A/C118F mutations, and systematically evaluated their cilia morphology and function, which were further validated in ARPE-19 cells...

The axoneme, a microtubule-based array at the center of every cilium, has been the subject of structural investigations for decades, but only recent advances in cryo-EM and cryo-ET have allowed a molecular-level interpretation of the entire complex to be achieved. The unique properties of the nine doublet microtubules and central pair of singlet microtubules that form the axoneme, including the highly decorated tubulin lattice and the docking of massive axonemal complexes, provide opportunities and challenges for sample preparation, 3D reconstruction and atomic modeling...

Surface-feeding aquatic animals navigate towards the source of water disturbances and must differentiate prey from other environmental stimuli. Medicinal leeches locate prey, in part, using a distribution of mechanosensory hairs along their body that deflect under fluid flow. Leech's behavioral responses to surface wave temporal frequency are well documented. However, a surface wave's temporal frequency depends on many underlying environmental and fluid properties that vary substantially in natural habitats (e...

Hyaluronan is an important extracellular matrix component, with poorly documented physiological role in the context of lipid-rich adipose tissue. We have investigated the global impact of hyaluronan removal from adipose tissue environment by in vitro exposure to exogenous hyaluronidase (or heat inactivated enzyme). Gene set expression analysis from RNA sequencing revealed downregulated adipogenesis as a main response to hyaluronan removal from human adipose tissue samples, which was confirmed by hyaluronidase-mediated inhibition of adipocyte differentiation in the 3T3L1 adipose cell line...

The primary cilium is an antenna-like projection from the plasma membrane that serves as a sensor of the extracellular environment and a crucial signaling hub. Primary cilia are generated in most mammalian cells, and their physiological significance is highlighted by the large number of severe developmental disorders or ciliopathies that occur when primary ciliogenesis is impaired. Primary ciliogenesis is a tightly regulated process, and a central early regulatory step is the removal of a key mother centriole capping protein, CP110 (also known as CCP110)...

Recent Studies have shown that the formation of the primary cilium is associated with a specific cellular organelle known as the midbody remnant(MBR), which is a point-like organelle formed by shedding of the midbody at the end of mitosis. MBRs move along the cell surface close to the center body, and regulate it to form primary cilia at the top of centriole. Primary cilia can act as an organelle to inhibit tumorigenesis, and it is lost in a variety of tumors. Studies have shown that the accumulation of MBRs in tumor cells affects ciliogenesis; in addition, both MBRs and primary cilia are degraded in tumor cells through the autophagy pathway, and MBRs can also transfer tumor signaling pathway factors to primary cilia affecting tumorigenesis...

The definitive demonstration of protein localization on primary cilia has been a challenge for cilia biologists. Primary cilia are solitary thread-like projections that contain specialized protein composition, but as the ciliary structure overlays the cell membrane and other cell parts, the identity of ciliary proteins are difficult to ascertain by conventional imaging approaches like immunofluorescence microscopy. Surface scanning electron microscopy combined with immuno-labeling (immuno-SEM) bypasses some of these indeterminacies by unambiguously showing protein expression in the context of the 3D ultrastructure of the cilium...

The efficient transport of proteins into the primary cilium is a crucial step for many signaling pathways. Dysfunction of this process can lead to the disruption of signaling cascades or cilium assembly, resulting in developmental disorders and cancer. Previous studies on the protein delivery to the cilium were mostly focused on the membrane-embedded receptors. In contrast, how soluble proteins are delivered into the cilium is poorly understood. In our work, we identify the exocyst complex as a key player in the ciliary trafficking of soluble Gli transcription factors...

In primary or idiopathic osteoarthritis (OA), it is unclear which factors trigger the shift of articular chondrocyte activity from pro-anabolic to pro-catabolic. In fact, there is a controversy about the aetiology of primary OA, either mechanical or inflammatory. Chondrocytes are mechanosensitive cells, that integrate mechanical stimuli into cellular responses in a process known as mechanotransduction. Mechanotransduction occurs thanks to the activation of mechanosensors, a set of specialized proteins that convert physical cues into intracellular signalling cascades...

BACKGROUND AND AIMS: Primary cilia (PC) are cellular organelles that regulate the cellular homeostasis. They are the seats of many oncogenic pathways and indirectly regulate the epithelial-mesenchymal transition (EMT) and extracellular matrix, both critical for the tumor microenvironment (TME). Though there are a few studies highlighting the alteration of PC in the tumor cells of various malignancies, none depict the PC in the stromal cells in the urothelial carcinoma of the urinary bladder (UC), the stromal cells being an essential component of TME...

Ciliary defects cause several ciliopathies, some of which have late onset, suggesting cilia are actively maintained. Still, we have a poor understanding of the mechanisms underlying their maintenance. Here, we show Drosophila melanogaste r IFT88 ( Dm IFT88/nompB) continues to move along fully formed sensory cilia. We further identify Inactive, a TRPV channel subunit involved in Drosophila hearing and negative-gravitaxis behaviour, and a yet uncharacterised Drosophila Guanylyl Cyclase 2d ( Dm Gucy2d/CG34357) as Dm IFT88 cargoes...

Airway epithelium, the first defense barrier of the respiratory system, facilitates mucociliary clearance against inflammatory stimuli, such as pathogens and particulates inhaled into the airway and lung. Inhaled particulate matter 2.5 (PM2.5 ) can penetrate the alveolar region of the lung, and it can develop and exacerbate respiratory diseases. Although the pathophysiological effects of PM2.5 in the respiratory system are well known, its impact on mucociliary clearance of airway epithelium has yet to be clearly defined...

Shear stress induced by urinary flow stimulates macroautophagy (hereafter referred to as autophagy) in kidney proximal tubule epithelial cells. Autophagy and selective degradation of lipid droplets by lipophagy contribute to tubule homeostasis by the production of ATP and control of epithelial cell size. Autophagy/lipophagy is controlled by a signaling cascade emanating from the primary cilium, localized at the apical side of epithelial cells. Downstream of the primary cilium, AMPK controls mitochondrial biogenesis on the one hand and autophagy/lipophagy on the other hand, which together increase fatty acid production that fuels oxidative phosphorylation to increase energy production...

The Southern Ocean and the Antarctic Circumpolar Current create environmental conditions that serve as an efficient barrier to prevent the colonization of non-native species (NNS) in the marine ecosystems of Antarctica. However, warming of the Southern Ocean and the increasing number of transport opportunities are reducing the physiological and physical barriers, increasing the chances of NNS arriving. The aim of this study was to determine the limits of survival of the juvenile mussels, M. chilensis, under current Antarctic conditions and those projected under climate change...

Primary cilia are rod-like sensory organelles that protrude from the surface of most mammalian cells, including the cells of the islet, and mounting evidence supports important roles of these structures in the regulation of beta cell function and insulin secretion. The sensory abilities of the cilium arise from local receptor activation that is coupled to intrinsic signal transduction, and ciliary signals can propagate into the cell and influence cell function. Here, we review recent advances and studies that provide insights into intra-islet cues that trigger primary cilia signalling; how second messenger signals are generated and propagated within cilia; and how ciliary signalling affects beta cell function...

Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. However, the molecular basis for HSC activation remains poorly understood. Herein, we demonstrate that primary cilia are present on quiescent HSCs but exhibit a significant loss upon HSC activation which correlates with decreased levels of the ciliary protein intraflagellar transport 88 (IFT88). Ift88-knockout mice are more susceptible to chronic carbon tetrachloride-induced liver fibrosis. Mechanistic studies show that the X-linked inhibitor of apoptosis (XIAP) functions as an E3 ubiquitin ligase for IFT88...