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      LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome

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          Abstract

          Primary cilia are sensory organelles crucial for cell signaling during development and organ homeostasis. Cilia arise from centrosomes and their formation and function is governed by numerous factors. Through our studies on Townes-Brocks Syndrome (TBS), a rare disease linked to abnormal cilia formation in human fibroblasts, we uncovered the leucine-zipper protein LUZP1 as an interactor of truncated SALL1, a dominantly-acting protein causing the disease. Using TurboID proximity labeling and pulldowns, we show that LUZP1 associates with factors linked to centrosome and actin filaments. Here, we show that LUZP1 is a cilia regulator. It localizes around the centrioles and to actin cytoskeleton. Loss of LUZP1 reduces F-actin levels, facilitates ciliogenesis and alters Sonic Hedgehog signaling, pointing to a key role in cytoskeleton-cilia interdependency. Truncated SALL1 increases the ubiquitin proteasome-mediated degradation of LUZP1. Together with other factors, alterations in LUZP1 may be contributing to TBS etiology.

          eLife digest

          Primary cilia are the ‘antennae’ of animal cells: these small, flexible protrusions emerge from the surface of cells, where they help to sense and relay external signals. Cilia are assembled with the help of the cytoskeleton, a dynamic network of mesh-like filaments that spans the interior of the cell and controls many different biological processes. If cilia do not work properly, human diseases called ciliopathies can emerge.

          Townes-Brocks Syndrome (TBS) is an incurable disease that presents a range of symptoms such as malformations of the toes or fingers, hearing impairment, and kidney or heart problems. It is caused by a change in the gene that codes for a protein called SALL1, and recent work has also showed that the cells of TBS patients have defective cilia. In addition, this prior research identified a second protein that interacted with the mutant version of SALL1; called LUZP1, this protein is already known to help maintain the cytoskeleton.

          In this study, Bozal-Basterra et al. wanted to find out if LUZP1 caused the cilia defects in TBS. First, the protein was removed from mouse cells grown in the laboratory, which dramatically weakened the cytoskeleton. In keeping with this observation, both the number of cilia per cell and the length of the cilia were abnormal. Cells lacking LUZP1 also had defects in a signalling process that transmits signals received by cilia to different parts of the cell. All these defects were previously observed in cells isolated from TBS patients. In addition, LUZP1-deficient mouse cells showed the same problems with their cilia and cytoskeleton as the cells from individuals with TBS. Crucially, the cells from human TBS patients also had much lower levels of LUZP1 than normal, suggesting that the protein may contribute to the cilia defects present in this disease.

          The work by Bozal-Basterra et al. sheds light on how primary cilia depend on the cytoskeleton, while also providing new insight into TBS. In the future, this knowledge could help researchers to develop therapies for this rare and currently untreatable disease.

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          Most cited references 63

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          Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.

          Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response, is a potential 'mechanism-based' therapeutic agent for treatment of these tumours. We show that cyclopamine or synthetic derivatives with improved potency block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.
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            Plk4-induced centriole biogenesis in human cells.

            We show that overexpression of Polo-like kinase 4 (Plk4) in human cells induces centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole. This provided an opportunity for dissecting centriole assembly and characterizing assembly intermediates. Critical components were identified and ordered into an assembly pathway through siRNA and localized through immunoelectron microscopy. Plk4, hSas-6, CPAP, Cep135, gamma-tubulin, and CP110 were required at different stages of procentriole formation and in association with different centriolar structures. Remarkably, hSas-6 associated only transiently with nascent procentrioles, whereas Cep135 and CPAP formed a core structure within the proximal lumen of both parental and nascent centrioles. Finally, CP110 was recruited early and then associated with the growing distal tips, indicating that centrioles elongate through insertion of alpha-/beta-tubulin underneath a CP110 cap. Collectively, these data afford a comprehensive view of the assembly pathway underlying centriole biogenesis in human cells.
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              A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.

              The centrosome is the primary microtubule organizing center of the cells and templates the formation of cilia, thereby operating at a nexus of critical cellular functions. Here, we use proximity-dependent biotinylation (BioID) to map the centrosome-cilium interface; with 58 bait proteins we generate a protein topology network comprising >7,000 interactions. Analysis of interaction profiles coupled with high resolution phenotypic profiling implicates a number of protein modules in centriole duplication, ciliogenesis, and centriolar satellite biogenesis and highlights extensive interplay between these processes. By monitoring dynamic changes in the centrosome-cilium protein interaction landscape during ciliogenesis, we also identify satellite proteins that support cilia formation. Systematic profiling of proximity interactions combined with functional analysis thus provides a rich resource for better understanding human centrosome and cilia biology. Similar strategies may be applied to other complex biological structures or pathways.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                18 June 2020
                2020
                : 9
                Affiliations
                [1 ]Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park DerioSpain
                [2 ]CIBERehd, Instituto de Salud Carlos III MadridSpain
                [3 ]ProteoRed-ISCIII, Instituto de Salud Carlos III MadridSpain
                [4 ]Department of Neurosciences, University of the Basque Country, Achucarro Basque Center for Neuroscience-UPV/EHU LeioaSpain
                [5 ]Analytical & High Resolution Biomedical Microscopy Core Facility, University of the Basque Country (UPV/EHU) LeioaSpain
                [6 ]Department of Chemistry, Massachusetts Institute of Technology CambridgeUnited States
                [7 ]Departments of Genetics, Chemistry and Biology, Stanford University StanfordUnited States
                [8 ]Chan Zuckerberg Biohub San FranciscoUnited States
                [9 ]Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) LeioaSpain
                [10 ]CIBERONC, Instituto de Salud Carlos III MadridSpain
                [11 ]Ikerbasque, Basque Foundation for Science BilbaoSpain
                [12 ]Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU) BilbaoSpain
                University of Copenhagen Denmark
                Utrecht University Netherlands
                University of Copenhagen Denmark
                Universität Heidelberg Germany
                Author notes
                [†]

                ITAV-CNRS, Centre Pierre Potier Oncopole, Toulouse, France.

                Article
                55957
                10.7554/eLife.55957
                7363444
                32553112
                © 2020, Bozal-Basterra et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: BFU2017-84653-P
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: SEV-2016-0644
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: SAF2017-90900-REDT
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: 765445-EU
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003086, Basque Government;
                Award ID: IT634-13
                Award Recipient :
                Funded by: Asociacion Espanola Contra el Cancer;
                Award ID: POSTD19048BOZA
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: PT13/0001/0027
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003086, Basque Government;
                Award ID: IKERTALDE IT1106-16
                Award Recipient :
                Funded by: Ministerio de Ciencia, Investigacion y Universidades;
                Award ID: SAF2016-79381-R
                Award Recipient :
                Funded by: Asociacion Espanola Contra el Cancer;
                Award ID: IDEAS175CARR
                Award Recipient :
                Funded by: Asociacion Espanola Contra el Cancer;
                Award ID: GCTRA18006CARR
                Award Recipient :
                Funded by: La Caixa Foundation;
                Award ID: ID 100010434, agreement LCF/PR/HR17
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: 336343
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: PoC 754627
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: 819242
                Award Recipient :
                Funded by: Ministerio de Economía y Competitividad;
                Award ID: RYC-2016-20480
                Award Recipient :
                Funded by: International Brain Research Organization;
                Award ID: ReturnHomeFellowship18-3
                Award Recipient :
                Funded by: Ministerio de Ciencia e Innovación;
                Award ID: RTI2018-097948-A-I00
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: PT13/0001/0027
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: CIBERehd
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Developmental Biology
                Custom metadata
                LUZP1 is required for proper cilia and cytoskeleton formation.

                Life sciences

                cilia, townes brocks syndrome, sall1, cytoskeleton, rare disease, centrosome, human, mouse

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