Your browser doesn't support javascript.
loading
LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome.
Bozal-Basterra, Laura; Gonzalez-Santamarta, María; Muratore, Veronica; Bermejo-Arteagabeitia, Aitor; Da Fonseca, Carolina; Barroso-Gomila, Orhi; Azkargorta, Mikel; Iloro, Ibon; Pampliega, Olatz; Andrade, Ricardo; Martín-Martín, Natalia; Branon, Tess C; Ting, Alice Y; Rodríguez, Jose A; Carracedo, Arkaitz; Elortza, Felix; Sutherland, James D; Barrio, Rosa.
Afiliación
  • Bozal-Basterra L; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Gonzalez-Santamarta M; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Muratore V; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Bermejo-Arteagabeitia A; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Da Fonseca C; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Barroso-Gomila O; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Azkargorta M; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Iloro I; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
  • Pampliega O; ProteoRed-ISCIII, Instituto de Salud Carlos III, Madrid, Spain.
  • Andrade R; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Martín-Martín N; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
  • Branon TC; ProteoRed-ISCIII, Instituto de Salud Carlos III, Madrid, Spain.
  • Ting AY; Department of Neurosciences, University of the Basque Country, Achucarro Basque Center for Neuroscience-UPV/EHU, Leioa, Spain.
  • Rodríguez JA; Analytical & High Resolution Biomedical Microscopy Core Facility, University of the Basque Country (UPV/EHU), Leioa, Spain.
  • Carracedo A; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
  • Elortza F; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States.
  • Sutherland JD; Departments of Genetics, Chemistry and Biology, Stanford University, Stanford, United States.
  • Barrio R; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States.
Elife ; 92020 06 18.
Article en En | MEDLINE | ID: mdl-32553112
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.
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.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ano Imperforado / Pulgar / Anomalías Múltiples / Citoesqueleto de Actina / Cilios / Proteínas del Citoesqueleto / Pérdida Auditiva Sensorineural Tipo de estudio: Prognostic_studies Límite: Adult / Animals / Humans / Male Idioma: En Revista: Elife Año: 2020 Tipo del documento: Article País de afiliación: España

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ano Imperforado / Pulgar / Anomalías Múltiples / Citoesqueleto de Actina / Cilios / Proteínas del Citoesqueleto / Pérdida Auditiva Sensorineural Tipo de estudio: Prognostic_studies Límite: Adult / Animals / Humans / Male Idioma: En Revista: Elife Año: 2020 Tipo del documento: Article País de afiliación: España
...