LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome
Laura Bozal‐Basterra, María Gonzalez-Santamarta, Veronica Muratore, Aitor Bermejo-Arteagabeitia, Carolina Da Fonseca, Orhi Barroso‐Gomila, Mikel Azkargorta, Ibón Iloro, Olatz Pampliega, Ricardo Andrade, Natalia Martín-Martín, Tess C. Branon, Alice Y. Ting, José Antonio Rodríguez, Arkaitz Carracedo, Félix Elortza, James D. Sutherland, Rosa Barrio
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.