Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules

• 成果类型: Article
• 署名作者: Dodd, Daniel O.; Mechaussier, Sabrina; Yeyati, Patricia L.; McPhie, Fraser; Anderson, Jacob R.; Khoo, Chen Jing; Shoemark, Amelia; Gupta, Deepesh K.; Attard, Thomas; Zariwala, Maimoona A.; Legendre, Marie; Bracht, Diana; Wallmeier, Julia; Gui, Miao; Fassad, Mahmoud R.; Parry, David A.; Tennant, Peter A.; Meynert, Alison; Wheway, Gabrielle; Fares-Taie, Lucas; Black, Holly A.; Mitri-Frangieh, Rana; Faucon, Catherine; Kaplan, Josseline; Patel, Mitali; McKie, Lisa; Megaw, Roly; Gatsogiannis, Christos; Mohamed, Mai A.; Aitken, Stuart; Gautier, Philippe; Reinholt, Finn R.; Hirst, Robert A.; O'Callaghan, Chris; Heimdal, Ketil; Bottier, Mathieu; Escudier, Estelle; Crowley, Suzanne; Descartes, Maria; Jabs, Ethylin W.; Kenia, Priti; Amiel, Jeanne; Bacci, Giacomo Maria; Calogero, Claudia; Palazzo, Viviana; Tiberi, Lucia; Bluemlein, Ulrike; Rogers, Andrew; Wambach, Jennifer A.; Wegner, Daniel J.; Fulton, Anne B.; Kenna, Margaret; Rosenfeld, Margaret; Holm, Ingrid A.; Quigley, Alan; Hall, Emma A.; Murphy, Laura C.; Cassidy, Diane M.; von Kriegsheim, Alex; Papon, Jean-Francois; Pasquier, Laurent; Murris, Marlene S.; Chalmers, James D.; Hogg, Claire; Macleod, Kenneth A.; Urquhart, Don S.; Unger, Stefan; Aitman, Timothy J.; Amselem, Serge; Leigh, Margaret W.; Knowles, Michael R.; Omran, Heymut; Mitchison, Hannah M.; Brown, Alan; Marsh, Joseph A.; Welburn, Julie P. I.; Ti, Shih-Chieh; Horani, Amjad; Rozet, Jean-Michel; Perrault, Isabelle; Mill, Pleasantine
• 署名单位: University of Edinburgh; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Harvard University; Harvard Medical School; University of Hong Kong; University of Dundee; Royal Brompton Hospital; Washington University (WUSTL); University of Edinburgh; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Assistance Publique Hopitaux Paris (APHP); Sorbonne Universite; Hopital Universitaire Armand-Trousseau - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; University of Munster; University of London; University College London; Egyptian Knowledge Bank (EKB); Alexandria University; University of Southampton; University of Edinburgh; University of Edinburgh; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris-Est-Creteil-Val-de-Marne (UPEC); Egyptian Knowledge Bank (EKB); Zagazig University; University of Oslo; National Hospital Norway; University of Leicester; University of Oslo; University of Oslo; National Hospital Norway; University of Alabama System; University of Alabama Birmingham; Icahn School of Medicine at Mount Sinai; Mayo Clinic; Birmingham Women's Hospital; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of Washington; University of Washington Seattle; Seattle Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; University of Edinburgh; University of London; Queen Mary University London; Harvard University; Harvard Medical School; Universite Paris Saclay; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Bicetre - APHP; CHU Rennes; Universite de Rennes; CHU de Toulouse; University of Edinburgh; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Washington University (WUSTL)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10787
• DOI: 10.1126/science.adf5489
• 发表日期: 2024-04-26
• 关键词: primary ciliary dyskinesia; beta-tubulin; choroid-plexus; cryo-em; mutations; platform; complex; cells

摘要

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type-and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in theTUBB4Bisotypethat specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies