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

eLife

Ibon Iloro¹  Natalia Martín-Martín¹  James D Sutherland²  Tess C Branon³  Olatz Pampliega³  Jose A Rodríguez⁴  Laura Bozal-Basterra⁵  Orhi Barroso-Gomila⁵  Mikel Azkargorta⁵  Aitor Bermejo-Arteagabeitia⁵  Carolina Da Fonseca⁵  María Gonzalez-Santamarta⁵  Ricardo Andrade⁵  Arkaitz Carracedo⁵  Veronica Muratore⁵  Felix Elortza⁶  Rosa Barrio⁶  Alice Y Ting⁷ 

[1] CIBERehd, Instituto de Salud Carlos III, Madrid, Spain;Departments of Genetics, Chemistry and Biology, Stanford University, Stanford, United States;ProteoRed-ISCIII, Instituto de Salud Carlos III, Madrid, Spain;Analytical & High Resolution Biomedical Microscopy Core Facility, University of the Basque Country (UPV/EHU), Leioa, Spain;Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain;Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States;Department of Neurosciences, University of the Basque Country, Achucarro Basque Center for Neuroscience-UPV/EHU, Leioa, Spain;

关键词: Cilia;    townes brocks syndrome;    SALL1;    cytoskeleton;    rare disease;    centrosome;   

DOI  :  10.7554/eLife.55957

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown