A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain

• Published in: Nature cell biology Vol. 14; no. 1; pp. 61 - 72
• Main Authors: Chih, Ben, Liu, Peter, Chinn, Yvonne, Chalouni, Cecile, Komuves, Laszlo G., Hass, Philip E., Sandoval, Wendy, Peterson, Andrew S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2012; Nature Publishing Group
• Subjects: Animals; Biology; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell Line; Cellular signal transduction; Cilia - metabolism; Cilia and ciliary motion; Cytoplasm - metabolism; Developmental Biology; Embryonic Stem Cells - metabolism; Gene Knockout Techniques; Genes; Genetic aspects; Genetics; Growth; Hedgehog Proteins - metabolism; Humans; Life Sciences; Localization; Membrane Microdomains - metabolism; Membrane proteins; Membrane Proteins - metabolism; Membranes; Mice; Mice, Inbred C57BL; Microscopy; NIH 3T3 Cells; Pathogenesis; Plasma; Properties; Proteins; Proteins - metabolism; RNA; Septins - metabolism; Signal Transduction; Stem Cells; Synthesis; United States; United States > US; South San Francisco California; California
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2410

Using RNAi screening, proteomics, cell biological and mouse genetics approaches, we have identified a complex of nine proteins, seven of which are disrupted in human ciliopathies. A transmembrane component, TMEM231, localizes to the basal body before and independently of intraflagellar transport in a Septin 2 (Sept2)-regulated fashion. The localizations of TMEM231, B9D1 (B9 domain-containing protein 1) and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the transition zone are dependent on one another and on Sept2. Disruption of the complex in vitro causes a reduction in cilia formation and a loss of signalling receptors from the remaining cilia. Mouse knockouts of B9D1 and TMEM231 have identical defects in Sonic hedgehog (Shh) signalling and ciliogenesis. Strikingly, disruption of the complex increases the rate of diffusion into the ciliary membrane and the amount of plasma-membrane protein in the cilia. The complex that we have described is essential for normal cilia function and acts as a diffusion barrier to maintain the cilia membrane as a compartmentalized signalling organelle. Peterson and colleagues find that the B9 complex localizes to the base of the primary cilia, where it functions as a ciliary diffusion barrier. Mutations in some B9 components are linked to human ciliopathies. The authors show that depleting components of the complex impairs primary cilia formation and inhibits the proper localization and function of signalling receptors in the cilia.