Journal Article

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

Carracedo, Arkaitz, Iloro, Ibon, Rodríguez, Jose A, Azkargorta, Mikel, Andrade, Ricardo, Da Fonseca, Carolina, Pampliega, Olatz, Elortza, Felix, Bermejo-Arteagabeitia, Aitor, Martín-Martín, Natalia, Barrio, Rosa, Bozal-Basterra, Laura, Barroso-Gomila, Orhi, Branon, Tess C, Sutherland, James D, Ting, Alice Y, Gonzalez-Santamarta, María, Muratore, Veronica

2020

Overview

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. 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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
• Subject: Abnormalities, Multiple / Abnormalities, Multiple - etiology / Abnormalities, Multiple - metabolism / Actin / Actin Cytoskeleton / Actin Cytoskeleton - metabolism / Adult / Animals / Antibodies / Anus, Imperforate / Anus, Imperforate - etiology / Anus, Imperforate - metabolism / Cell Biology / Cell cycle / Cells (Biology) / Centrioles / Centrosome / Centrosome - metabolism / Centrosomes / Cilia / Cilia - metabolism / Cytoskeletal Proteins / Cytoskeletal Proteins - metabolism / Cytoskeletal Proteins - physiology / Cytoskeleton / Defects / Developmental Biology / Etiology / Experiments / Fibroblasts / Fibroblasts - metabolism / Filaments / Hearing Loss, Sensorineural / Hearing Loss, Sensorineural - etiology / Hearing Loss, Sensorineural - metabolism / Hedgehog protein / Homeostasis / Humans / Leucine zipper proteins / Life Sciences / Male / Medical research / Mice / Molecular weight / Mutation / Organelles / Proteasomes / Proteins / Proteomics / rare disease / Rare diseases / SALL1 / Thumb / Thumb - abnormalities / Townes-Brocks syndrome / Transcription Factors / Transcription Factors - metabolism / Ubiquitin