LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome
- CIC bioGUNE, Spain
- Achucarro Basque Center for Neuros, Spain
- University of the Basque Country (UPV/EHU), Spain
- Stanford University, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Ministerio de Economía y Competitividad (BFU2017-84653-P)
- Rosa Barrio
Asociacion Espanola Contra el Cancer (IDEAS175CARR)
- Arkaitz Carracedo
Asociacion Espanola Contra el Cancer (GCTRA18006CARR)
- Arkaitz Carracedo
La Caixa Foundation (HR17-00094)
- Arkaitz Carracedo
European Commission (336343)
- Arkaitz Carracedo
European Commission (PoC 754627)
- Arkaitz Carracedo
European Commission (819242)
- Arkaitz Carracedo
Ministerio de Economía y Competitividad (SEV-2016-0644)
- Arkaitz Carracedo
- Felix Elortza
- James D Sutherland
- Rosa Barrio
Ministerio de Economía y Competitividad (SAF2017-90900-REDT)
- Rosa Barrio
European Commission (765445-EU)
- Orhi Barroso-Gomila
- James D Sutherland
- Rosa Barrio
Basque Government (IT634-13)
- Arkaitz Carracedo
Asociacion Espanola Contra el Cancer (POSTD19048BOZA)
- Arkaitz Carracedo
Instituto de Salud Carlos III (PT13/0001/0027)
- Arkaitz Carracedo
Basque Government (IKERTALDE IT1106-16)
- Arkaitz Carracedo
Ministerio de Ciencia, Investigacion y Universidades (SAF2016-79381-R)
- Arkaitz Carracedo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The use of human samples in this study was approved by the institutional review board (Ethics Committee at CIC bioGUNE) and appropriate informed consent was obtained from human subjects or their parents. protocol P-CBG-CBBA-2111)
Reviewing Editor
- Lotte Pedersen, University of Copenhagen, Denmark
Publication history
- Received: February 12, 2020
- Accepted: June 18, 2020
- Accepted Manuscript published: June 18, 2020 (version 1)
- Version of Record published: July 15, 2020 (version 2)
Copyright
© 2020, Bozal-Basterra et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome
eLife 9:e55957.
https://doi.org/10.7554/eLife.55957
Further reading
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Meiotic chromosome segregation relies on synapsis and crossover recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in 'homolog engagement' is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans, recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break induction. Inactivation of CHK-2 terminates double-strand break formation and enables crossover designation and cell cycle progression. These findings illuminate how meiotic cells ensure crossover formation and accurate chromosome segregation.
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Motile cilia are hair-like cell extensions that beat periodically to generate fluid flow along various epithelial tissues within the body. In dense multiciliated carpets, cilia were shown to exhibit a remarkable coordination of their beat in the form of traveling metachronal waves, a phenomenon which supposedly enhances fluid transport. Yet, how cilia coordinate their regular beat in multiciliated epithelia to move fluids remains insufficiently understood, particularly due to lack of rigorous quantification. We combine experiments, novel analysis tools, and theory to address this knowledge gap. To investigate collective dynamics of cilia, we studied zebrafish multiciliated epithelia in the nose and the brain. We focused mainly on the zebrafish nose, due to its conserved properties with other ciliated tissues and its superior accessibility for non-invasive imaging. We revealed that cilia are synchronized only locally and that the size of local synchronization domains increases with the viscosity of the surrounding medium. Even though synchronization is local only, we observed global patterns of traveling metachronal waves across the zebrafish multiciliated epithelium. Intriguingly, these global wave direction patterns are conserved across individual fish, but different for left and right nose, unveiling a chiral asymmetry of metachronal coordination. To understand the implications of synchronization for fluid pumping, we used a computational model of a regular array of cilia. We found that local metachronal synchronization prevents steric collisions, cilia colliding with each other, and improves fluid pumping in dense cilia carpets, but hardly affects the direction of fluid flow. In conclusion, we show that local synchronization together with tissue-scale cilia alignment coincide and generate metachronal wave patterns in multiciliated epithelia, which enhance their physiological function of fluid pumping.
